Map of Pancreatica Walks and Runs

The Relationship Between Diabetes and Pancreatic Cancer

“It’s complicated.”  But why should pancreatic cancer be any less convoluted than other aspects of the pancreas?  The origin of the embryologic pancreas develops from TWO buds off of the foregut – that EACH “typically” moves and develops, eventually merging to form what we know as the pancreas.  This somewhat individualistic merging process alone produces many anatomic anomalies, as any experienced pancreatic cancer surgeon will tell you.  Also, separately, the function of the pancreas is complicated, divided roughly into exocrine (digestive juice producing) and endocrine (the hormone producing “islet”) areas.

Pancreatic cancer can arise literally from virtually any type of cell in the pancreas. The most common kind, that which has such a rough prognosis arises in the duct lining cells that line the pathways that carry digestive juice downstream (left to right) eventually usually combining with bile juice (at the bile duct junction) to deposit the combined product, so useful for ordinary digestion, into the first (duodenal) portion of the small bowel. This type of tumor then is called pancreatic ductal adenocarcinoma.

And what are we to make of the general observation of this relationship between this form of pancreatic cancer and what seems empirically to be an increased association of the onset of diabetes?  After all, they are from completely different functional areas of the pancreas. Is this association real, or a form of recollection bias?  If so, is diabetes mellitus a cause of ductal pancreatic cancer – or a result of it?

This is the vineyard in which Nikfarjam and his surgical colleagues at the University of Melbourne in Australia have been working in regard to their recent study published on March 9, 2014 in the Annals of Surgical Oncology.  The researchers tried to better quantify the strength of the association between diabetes and pancreatic cancer over time, and to better qualify the relationship.  After reviewing forty years of published medical articles as found in electronic databases (1973 through 2013), the authors identified eighty-eight studies that met their criteria. These included fifty cohort studies and thirty-three case-study studies involving the onset of diabetes and the risk of pancreatic cancer.

They found that the relative risk overall between the onset of newly diagnosed diabetes mellitus was statistically significant but at a reasonably modest 1.77.  Though through a consideration of time as a factor, the authors conclusions demonstrated a more complex picture. They found that the closer in time to the diagnosis of diabetes: the more likely the discovery of pancreatic cancer.  So, for example, the researchers calculated the relative risk at less than one year at 6.69 (the pancreatic cancer occurred nearly seven times more frequently than what one might expect), but that this factor dropped such that at ten years the relative risk was only 1.36.

This is a lovely study that further quantifies the elusive relationship between diabetes and ductal pancreatic cancer. There are still many questions, and it leaves the chicken versus egg question unsolved.  But increasingly the evidence mounts that during the year or two or more after the onset of diabetes mellitus, a pancreatic cancer diagnosis is much more likely.  That this is a high risk period that demands heightened clinical scrutiny.

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Dale O’Brien, MD

 

Hedgehog Pathway Inhibition Slows Pancreatic Cancer Cell Growth

You may wonder what this has to do with pancreatic cancer, but please know that those of us who are old enough to remember once shivered and screamed in horror at the 1958 move, The Fly, whereby the protagonist ended up half human, half housefly (musca domestica).  This fear may not be too far from the truth, as the evolution of human DNA may include remnants of our flying antagonists.

In 1995, three biologists (Lewis, Nüsslein-Volhard and Wieschaus) shared the Noble Prize in Medicine for their work beginning in the late 1970s in studying genetic mutations related to body segmentation in the development of the fruit fly (Drosophila), including the identification of the three “hedgehog” genes related to this process. The name “hedgehog” was given as a result of the stubby and especially disordered and hairy look of the mutated drosophila denticles on the mutated larvae.

Not only are hedgehog genes active in flies, but their actions are integral to normal development in human embryos.  Also, the complex hedgehog signaling pathway appears to have key but not fully understood mechanisms in human adults, including the production of adult stem cells. Disruption of this signalling pathway can cause severe birth defects, miscarriage, and death. And the adult activation of the hedgehog pathway (overexpression of its components) appears to be related to the development of a number of especially difficult cancers, including pancreatic cancer. It is thought that undue activation of the hedgehog signaling pathway may transform the adult stem cells (generally: good) into specific cancer stem cells (generally: bad, as they may cause, protect and/or abet the rapid growth of the tumor).

Professor Tony Magee and researchers from the Imperial College London (along with a Danish colleague) and based on a grant from the UK’s Pancreatic Cancer Research Fund, on March 7, 2014 published the results of their pre-clinical work in the journal PLoS.  The researchers inhibited the effect of “hedgehog acyltransferase” in pancreatic cancer cells, an enzyme that appears to be critical in the signaling pathway.  As suspected, the result was that the growth and spread of the pancreatic cancer tumor cells were severely curtailed.

The authors’ conclusions were that hedgehog acyltransferase is in fact a key component of the hedgehog pathway, and that its amelioration may help impede pancreatic cancer growth and spread.

This careful and thoughtful work is early stage, but may prompt an important angle of attack by way of future pancreatic cancer research leading to clinical trials.

 

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Dale O’Brien, MD

Scientific Framework for Pancreatic Cancer

In February of this year the U.S. National Cancer Institute published an important overview of the state of the science and medicine of pancreatic cancer.  We will comment on aspects of it from time to time in the future, but as it so comprehensive and precise, in a departure from our usual practice, we will show a copy it here (sans bibliography and figures) in our pancreatic cancer blog.  The term “Pancreatic Ductal Carcinoma” is accurate and abbreviated PDAC in the original paper; here in the interests of a potential lay reader we will add in parentheses the term: pancreatic cancer.

Scientific Framework for Pancreatic Ductal Carcinoma

Executive Summary

Significant scientific progress has been made in the last decade in understanding the biology and natural history of pancreatic ductal adenocarcinoma (PDAC, pancreatic cancer); major clinical advances, however, have not occurred. Although PDAC (pancreatic cancer) shares some of the characteristics of other solid malignancies, such as mutations affecting common signaling pathways, tumor heterogeneity, development of invasive malignancy from precursor lesions, inherited forms of the disease, and common environmental risk factors, there are unique obstacles that have made progress against PDAC (pancreatic cancer) difficult. These include: diagnosis at a late stage in the disease because of a lack of specific symptoms or biomarkers to facilitate early diagnosis, and the anatomical location of the pancreas; metastatic spread when the primary tumor is too small to detect by current methods; dynamic interaction of the tumor with stromal cells creating dense fibrous tissue around the tumor that contributes to therapeutic resistance; and the small percentage of patients for whom curative surgery is a feasible option.

The Recalcitrant Cancer Research Act of 2012 (Public Law 112-239, §1083) calls upon the National Cancer Institute (NCI) to “develop scientific frameworks” that will assist in making “progress against recalcitrant or deadly cancers.” PDAC (pancreatic cancer) is a recalcitrant cancer as defined by its five-year relative survival rate of less than 5 percent that translates into the loss of almost 40,000 lives per year. Consensus within the scientific community regarding the limited early diagnostic or therapeutic approaches for patients with PDAC (pancreatic cancer) has provided a stimulus for the evaluation of new and missed opportunities that could now be applied to the existing portfolio of PDAC (pancreatic cancer) research in order to make more substantial progress.

The current state of knowledge in PDAC (pancreatic cancer) research, including epidemiology, risk assessment, pathology, screening, early detection, and therapeutic research was evaluated by an expert panel of extramural scientists that helped the NCI identify and prioritize new scientific ideas, technologies, and resources that might advance the field and improve the outlook both for patients with PDAC (pancreatic cancer) and for individuals at high risk of developing the disease. Four investigational initiatives developed by this group of experts were recommended for consideration by the NCI to incorporate within the existing research portfolio for PDAC (pancreatic cancer): (1) development of an in-depth understanding of the biological and clinical relationship between PDAC (pancreatic cancer) and diabetes mellitus of recent onset; (2) evaluation of longitudinal screening protocols, concomitant with the development of new molecular and imaging biomarkers, for patients at high risk for PDAC (pancreatic cancer) because of genetic factors or the presence of mucinous pancreatic cysts who could be candidates for early surgical intervention; (3) implementation of new immunotherapy approaches based on a deeper understanding of how PDAC (pancreatic cancer) interacts with its potentially immunosuppressive microenvironment; and (4) development of new treatment strategies that interfere with RAS oncogene-dependent signaling pathways.

Plans for implementation of these recommended initiatives, within the context of NCI’s current research framework for PDAC (pancreatic cancer), have been developed. In addition, an overall process for evaluating progress and providing oversight for the NCI’s PDAC (pancreatic cancer) research portfolio is in place to meet the goals of the Recalcitrant Cancer Research Act of 2012.

 

Introduction

The Recalcitrant Cancer Research Act of 2012 (Public Law 112-239 §1083) defines recalcitrant cancers as those cancers with a five-year survival rate below 50 percent. The Act requires the NCI to identify two or more recalcitrant cancers that have a five-year relative survival rate of less than 20% and cause more than 30,000 deaths per year in the United States and to develop a scientific framework for the conduct or support of research for each of these cancers.

This report, prepared by the NCI, National Institutes of Health (NIH), for submission to Congress and posting on the Department of Health and Human Services (DHHS) website, focuses on the NCI’s scientific framework for pancreatic ductal adenocarcinoma (PDAC or pancreatic cancer). This report fulfills the provision of the Act that the NCI develop a scientific framework for the first of two identified recalcitrant cancers within 18 months of enactment (by July 2, 2014). The scientific framework will be sent to Congress and made available publicly on the website within 30 days of completion. A separate report from a workshop held at the NCI on October 23 and 24, 2012, that was attended by the NCI Director and other Federal and non-Federal experts, and that was conducted to assist with the expansion of the NCI’s existing scientific framework for PDAC (pancreatic cancer).

 

Background

Pancreatic cancers are a group of heterogeneous diseases of both the endocrine and exocrine pancreas. PDAC (pancreatic cancer), an exocrine tumor, represents over 90% of all pancreatic malignancies1. Endocrine tumors of the pancreas, such as those that arise from pancreatic islets, represent 3­5% of pancreatic neoplasms; endocrine tumors are a distinct class of cancers that must be differentiated both pathologically and clinically from PDAC (pancreatic cancer). Although PDAC (pancreatic cancer) is a relatively rare tumor (2% of all cancer cases), it is the fourth leading cause of cancer death in the United States with an average survival time after diagnosis of less than one year. The incidence of PDAC (pancreatic cancer) increases with age, with a median age of 71 years at diagnosis. It has been estimated that there will be 45,220 new cases of PDAC (pancreatic cancer) in the U.S. in 2013 with 38,460 deaths from PDAC (pancreatic cancer) in the same period; the incidence of PDAC (pancreatic cancer) has been rising slowly from 1982 to 2008  (http://www.cancer.gov/researchandfunding/reports/pancreatic-research-progress.pdf).

The average lifetime risk for developing PDAC (pancreatic cancer) is about 1/78 for both men and women2. Globally, 70% of all pancreatic cancer cases occur in people living in advanced economies, with over 270,000 deaths per year worldwide3. Approximately 10% of PDAC (pancreatic cancer)s occur in families with a history of PDAC (pancreatic cancer)4; some occur in association with other cancers or diseases, but most do not occur in association with a defined syndrome5. The overwhelming majority of PDAC (pancreatic cancer) cases are sporadic, that is, occurring without a history of the disease in first degree relatives.

Although much is known about the evolution of PDAC (pancreatic cancer) from its earliest non-malignant precursor lesions, PDAC (pancreatic cancer) cases are most often diagnosed at late stages: about 30% of patients have locally advanced disease and over 50% have metastases at distant sites when the disease is first diagnosed. Early detection has been problematic because of the absence of specific symptoms, the insufficiency of serological biomarkers with appropriate sensitivity and specificity, the lack of a clinically practical diagnostic examination for the disease, and the retroperitoneal position of the pancreas. Unlike many other malignant diseases, the metastatic spread of PDAC (pancreatic cancer) is thought to begin when the primary tumor is approximately 10 mm in size, when results of routine non-invasive imaging are often equivocal or negative5. Currently, surgery (pancreaticoduodenectomy) provides the only possible curative therapy for PDAC (pancreatic cancer); but less than 20% of patients are suitable candidates for this difficult procedure because the disease has already spread. Overall, surgery produces long-term, disease-free survival in only 3-4% of all individuals presenting with this disease—generally in patients with “early” PDAC (pancreatic cancer) (i.e., tumors < 20 mm) and without tumor involvement in the surgical margins at resection. Evidence comparing stage of disease with outcome following surgery suggests that death rates for PDAC (pancreatic cancer) would be reduced if the disease could be diagnosed at an earlier stage6,7 . Since genomic sequencing data from primary and metastatic PDAC (pancreatic cancer)s indicate that it takes approximately 17 years for PDAC (pancreatic cancer) to progress from the tumor-initiating cell to the development of metastatic disease8, it would appear that there is ample time to diagnose and intervene, if diagnostic barriers to earlier detection could be overcome.

 

Summary of the Literature and Recent Advances

Biology and Genetics:

PDAC (pancreatic cancer)s arise from a ductal cell lineage or from acinar cells that undergo acinar-to-ductal metaplasia9. Pancreatic intraepithelial neoplasms (PanINs) are the most common precursors to PDAC (pancreatic cancer), and are often found associated with areas of focal pancreatic inflammation. Certain cystic lesions of the pancreas are also premalignant: pancreatic intraductal papillary mucinous neoplasms (IPMNs) are found equally in men or women in their 60s and often communicate directly with the main pancreatic duct; mucinous cystic neoplasms (MCNs), which are overwhelmingly found in women in their late 40s10, are often solitary cystic lesions in the body or tail of the pancreas. Virtually all PanINs, even the earliest type, PanIN-1, harbor KRAS mutations. Mutant KRAS alleles show increased expression as PanIN-1 evolves to intermediate PanIN-2, and then to the carcinoma in situ lesion, PanIN-3. The few precursor lesions that do not contain mutant KRAS often have mutations in other genes in the KRAS signaling pathway, such as those in BRAF13. Loss of CDKN2A, a tumor suppressor, is also found in some early PanINs. It is now thought that a KRAS mutation is necessary, but not sufficient, to drive PanINs to PDAC (pancreatic cancer). Recent studies, however, have shown that in mutant KRAS-driven PDAC (pancreatic cancer)s, KRAS is required at all states of pancreatic carcinogenesis and for subsequent tumor maintenance. KRAS is mutated in approximately 95% of all PDAC (pancreatic cancer)s— the highest percentage of all solid malignancies1.  Besides mutated KRAS and the loss of CDKN2A (often referred to by the protein it encodes, INK4a p16), genetic alterations have been found in tumor suppressor genes SMAD4 (also termed DPC4) and TP53. A more detailed genomic analysis of a large number of PDAC (pancreatic cancer)s has uncovered an average of 63 genetic alterations, mostly point mutations, which affect up to 12 different signaling pathways or processes17. These include alterations in apoptosis pathways, hedgehog signaling, regulation of invasion, and signaling via KRAS, TGF-β, and Wnt or Notch. The expression of sonic hedgehog protein (a ligand of the hedgehog pathway) in both early and late PDAC (pancreatic cancer) lesions has been implicated as a chemoattractant in the desmoplastic response (a host stromal response resulting in the proliferation of fibrotic tissue with an altered extracellular matrix and a pronounced hypovascularity)18.

 

Risk Assessment and Screening:

Risk assessment studies have been performed associating germline susceptibility genes with the development of PDAC (pancreatic cancer). Many of these case-control studies were performed using registries of families with a strong history of pancreatic cancer. Individuals in these families can have up to a 13-fold increase in risk. Mutations in the following germline genes appear to have a role in susceptibility to PDAC (pancreatic cancer) although most do not have a high penetrance: BRCA2, STK11, PALB2, ATM, and CDKN2A. In addition, mutations in PRSS1 and SPINK1 are associated with susceptibility for hereditary pancreatitis, which greatly increases the risk for PDAC (pancreatic cancer). Other hereditary diseases and syndromes have also been shown to increase risk for PDAC (pancreatic cancer); individuals with these syndromes often harbor mutations in the genes that confer risk for PDAC (pancreatic cancer). Studies of the gene alterations in high risk individuals could also be important in informing studies of sporadic PDAC (pancreatic cancer) and lead to a better understanding of the etiology of the disease.

Among the known non-genetic risk factors are: tobacco use; age; obesity; chronic pancreatitis, including hereditary pancreatitis; and diabetes, both long-term type 2 diabetes and especially new-onset diabetes, which may be an early consequence of PDAC (pancreatic cancer) itself3,20 .

It has become clear that early detection of small resectable lesions, particularly pre-neoplastic lesions such as PanINs (2 and 3) and IPMNs or MCNs is the best hope for increasing the overall survival in this disease, since locally advanced and metastatic PDAC (pancreatic cancer)s are relatively insensitive to chemotherapy or radiation therapy, and surgical resection is often followed by relapses. So far, no serum or tumor-based biomarkers or biomarker panels have been discovered that are both sensitive and specific enough for accurate early detection. CA19.9 is the most commonly used tumor biomarker for monitoring therapeutic progress in PDAC (pancreatic cancer), but the lack of specificity of the assay is a concern, and CA19.9 therefore cannot be used for early detection. Progress in this area will have to come from new diagnostic discoveries—perhaps employing circulating tumor cells, tumor-derived DNA, autoantibodies, miRNA profiles, cytokines and chemokines, and from specific genetic, epigenetic, or proteomic signatures. Advances in non-invasive imaging technology that can detect tumors or pre-cancerous pancreatic lesions as small as 0.5 mm will also be needed. Invasive imaging such as endoscopic ultrasound can detect most pancreatic cysts, and targeted imaging agents have been shown to detect PanIN-3 lesions24. These methods of detection are expensive and cannot be used for routine screening, but could be employed in high risk individuals.

One approach is to focus screening efforts on the groups of asymptomatic individuals who have been shown to have a higher risk of PDAC (pancreatic cancer) than the general population: those with hereditary risk factors, environmental risk factors, or other diseases that increase the odds of developing PDAC (pancreatic cancer). The risk relationship between long-standing type 2 diabetes and PDAC (pancreatic cancer), based on epidemiological evidence, is well-known as is the increased risk of PDAC (pancreatic cancer) in patients with newly-diagnosed diabetes; the relative risk estimate for patients diagnosed with diabetes at least five years prior to a diagnosis of PDAC (pancreatic cancer) is 2.0 (95% confidence interval, 1.2 to 3.2)25. As reviewed in the Workshop Report: Pancreatic cancer: Scanning the Horizon for Focused Interventions (Appendix 1), recent evidence suggests that screening for PDAC (pancreatic cancer) in patients with specific subtypes of diabetes, such as those newly diagnosed, and particularly in association with other risk factors (such as genetic predisposition or tobacco use), may be a particularly fruitful approach to early detection.

 

Models of PDAC (pancreatic cancer):

The development of new, clinically-relevant treatment approaches for PDAC (pancreatic cancer) can benefit greatly from testing in appropriate animal models—ones that display the evolution of PDAC (pancreatic cancer) from the earliest lesion to frank PDAC (pancreatic cancer), both morphologically and genetically, and demonstrate the hallmark features of the disease: intratumoral heterogeneity, dense desmoplasia, and early spontaneous metastases. Mouse xenografts using cultured PDAC (pancreatic cancer) cells are minimally useful because, although they often retain the key genetic alterations in signaling pathways of PDAC (pancreatic cancer), they lack the early carcinogenic stages of the disease (when treatment might be most effective), do not exhibit a natural disease progression, and are missing the immunological and other stromal components of the tumor-host interaction normally seen in the human disease. Mutant KRAS-driven genetically engineered mouse models (GEMMs) that recapitulate key aspects of human PDAC (pancreatic cancer), including non-invasive precursor lesions, have now become some of the most important tools for the study of PDAC (pancreatic cancer) development and invasion, as well as preclinical testing of novel therapeutic approaches. The introduction of additional altered genes that are important in progression from early lesions to invasive PDAC (pancreatic cancer) has enabled the construction of specific models that faithfully follow the development of PDAC (pancreatic cancer) from PanINs or pancreatic cysts. It has recently been shown, using these models, that canonical Wnt/β catenin pathway activation can encode pancreatic carcinogenesis as early as the PanIN stage33. One caveat in the use of these models is that the altered KRAS allele, KRASG12D, is activated during embryogenic pancreatic development, which is probably not an event likely to occur in patients who later develop PDAC (pancreatic cancer)31. Nonetheless, the Pdx1-Cre;KrasG12D and the PTF1a+/Cre; KrasG12D models show a spectrum of PanINs and/or pancreatic cysts, long latency, late onset of PDAC (pancreatic cancer), and frequent metastases, and can be further manipulated to speed disease progression.

 

Therapy and Resistance:

For over a decade, gemcitabine or gemcitabine in combination with other chemotherapy agents has been the standard of care for advanced PDAC (pancreatic cancer)34. In 2011, FOLFIRINOX (oxaliplatin, irinotecan, leucovorin, and 5-FU) was shown to provide a modest increase in overall survival, although the toxicity was greater35. The addition of molecularly targeted therapies has been evaluated; to date, only erlotinib, targeting the EGF receptor, has demonstrated a modest, albeit statistically significant, response rate in combination with gemcitabine. The recent elucidation of alterations in the various signaling pathways in PDAC (pancreatic cancer) and in pancreatic cancer stem-like cells may lead to the testing of new agents and combinations in the future, and to defining the patient populations that might benefit from targeted systemic therapy.

Resistance to therapy is a characteristic feature of PDAC (pancreatic cancer), and the extent of resistance is greater than in many other human tumors. This could be due to inefficient drug delivery, intrinsic and acquired resistance of the tumor, tumor hypoxia, or the insensitivity of cancer stem-like cells to currently used agents. It is thought that the dense desmoplasia produced by the dynamic interaction of stromal cells with the tumor, and which constitutes 90% of the tumor volume, creates a barrier to systemic drug delivery and penetration38. Novel approaches employing newly-developed biological molecules, discussed in the next section, may provide a means to overcome therapeutic resistance in patients with PDAC (pancreatic cancer).

 

NCI’s Current Research and Framework for PDAC (pancreatic cancer)

The NCI supports major, ongoing efforts to advance the scientific understanding of the cause(s) of PDAC (pancreatic cancer), to develop new tools for early diagnosis, and to devise more effective therapeutic interventions. These existing research programs, (described in the 2011 National Cancer Institute Action Plan for Pancreatic cancer http://www.cancer.gov/researchandfunding/reports/pancreatic-research-progress.pdf), formed the scientific foundation from which new areas of emphasis were developed by the recent PDAC (pancreatic cancer) workshop.

Basic PDAC (pancreatic cancer) Biology:

The NCI currently supports research programs dedicated to advancing progress in understanding the basic biology of PDAC (pancreatic cancer). These programs involve studies to further elucidate the biology of the normal pancreas, including interdisciplinary approaches to understand islet cell development and function, the characterization of signaling pathways suspected to play a role in the development of PDAC (pancreatic cancer), and large-scale genomic studies, including those of The Cancer Genome Atlas, that are developing a detailed understanding of the molecular underpinnings of PDAC (pancreatic cancer) development and evolution. Studies of the interactions between the microenvironment within which PDAC (pancreatic cancer)s develop and host factors, such as the response of the immune system to inflammatory stress, are attempting to understand the biological alterations that play an essential role in the progression of early PanIN lesions to PDAC (pancreatic cancer).

Risk, Prevention, Screening, and Diagnosis:

The NCI provides resources for epidemiologic studies, including those involving several case-control and cohort consortia, to determine the role of environmental and genetic factors on the risk of developing PDAC (pancreatic cancer). These investigations examine the influence of smoking, obesity, and physical activity on PDAC (pancreatic cancer) development. Several studies are also evaluating the potential of dietary factors to prevent or modify the initiation and progression of PDAC (pancreatic cancer).

Efforts to develop new diagnostic markers in serum for the early detection of PDAC (pancreatic cancer) are ongoing. Improving the capabilities of several different imaging techniques to enhance their sensitivity, enabling the detection of pre-neoplastic pancreatic cysts and small tumors that would both be amenable to complete surgical resection, is also a priority. Diagnostic and screening studies are being

pursued both in laboratory models and through the expansion of registries for patients and families at high risk of developing PDAC (pancreatic cancer).

Treatment:

Because of the ineffectiveness of most current therapies, the NCI is investing in a wide range of approaches to improve the treatment of PDAC (pancreatic cancer). These approaches are being pursued both in preclinical model systems and in clinical trials. Emphasis has been placed on understanding whether specific signaling pathways can be targeted for therapeutic benefit in PDAC (pancreatic cancer). In particular, studies attempting to interfere with the dense stromal reaction that interferes with the delivery of therapeutic agents to both PDAC (pancreatic cancer) cells and the surrounding microenvironment (including new nanoparticle drug formulations) hold the promise of overcoming resistance to currently-available agents. In addition to drugs targeting specific molecular pathways, biological therapies are under study. Biological treatments being evaluated in animal models and patients include: vaccines (incorporating highly immunogenic tumor-specific antigenic targets); monoclonal antibodies and other direct targeting agents such as immunotoxins; adoptive cellular therapies, particularly in patients with resectable tumors; various gene therapy methodologies; and oncolytic viruses (replicative competent viruses with selective tropisms for tumors but not normal cells). One biological approach currently supported by the NCI that is of major interest has been the adoptive transfer of genetically modified T lymphocytes that express a chimeric antigen receptor (CAR), an approach that has demonstrated significant therapeutic benefit in preclinical models of PDAC (pancreatic cancer)46.

Patients with PDAC (pancreatic cancer) often experience debilitating symptoms that markedly diminish their quality of life. The degree of pain, fatigue, or anorexia that commonly accompanies PDAC (pancreatic cancer) often prevents the administration of standard treatment or participation in clinical trials. Thus, ongoing efforts to understand the etiology of and to develop treatment for fatigue and cachexia are important components of NCI-supported clinical research in the area of symptom management.

Training:

NCI has recognized the need for a dedicated workforce to conduct pancreatic cancer research across a wide range of investigational topics. Research training in the area of PDAC (pancreatic cancer) has grown substantially over the past decade and now supports investigators in pre-doctoral and post­doctoral positions, as well as independent early-career scientists and clinical trialists. NCI-supported scientists are being trained to investigate the biology, epidemiology, and genetics of PDAC (pancreatic cancer) and other malignancies, as well as combined modality approaches to treatment and the development of clinical trials with targeted agents, and the signal transduction pathways involved in drug resistance for these diseases.

Support for PDAC (pancreatic cancer) Research by NCI: Grants, Contracts and Cooperative Agreements:

To support this ongoing research framework, the NCI invested $105 million in fiscal year 2012 for pancreatic cancer research, a 5-fold increase since 2000 ($20 million; Figure 1). This investment includes funding in the form of grants, cooperative agreements, and contracts to extramural scientists and trainees (93%) and to NCI intramural investigators (7%) involved in basic, pre-clinical, translational, and clinical pancreatic cancer research. Awards have been made to support traditional investigator-initiated R01 research, Program Project Grants, Cancer Center Support Grants, Specialized Programs of Research Excellence (SPOREs), and other P50 grants, exploratory/development grants, small business awards, training and fellowship grants, cooperative agreements, intramural research, and other funding mechanisms (Figure 2).

The number of investigators supported by R01 grants for pancreatic cancer research has also increased since 2000 (Figure 3). Realizing that it is important to attract to the field new investigators (those who have never obtained a substantial NIH independent research award) and early stage investigators (new investigators who are, in addition, within 10 years of completing a terminal degree or a medical residency), the NCI has made an effort to fund these investigators who are embarking on a career in pancreatic cancer research. Figure 4 shows the number of extramural scientists who received pancreatic cancer research funding, utilizing all mechanisms, from the NCI in 2012. Although the majority of the grants were awarded to experienced investigators, a significant number of grants were awarded to new and early stage investigators, and most of these grants had 100% relevance to pancreatic cancer. As one might expect, the total number of dollars awarded to new and early stage investigators studying PDAC (pancreatic cancer) is considerably less than that awarded to experienced investigators because many of the new awardees obtain fellowship, training, and exploratory grants, which have lower cost caps. Table 1 contains a list of the funding mechanisms and numbers of grants awarded to the next generation of researchers who are working on PDAC (pancreatic cancer) and supported by the NCI. The full data can be reviewed using the following link: http://tiny.cc/deyv7w

If one considers NCI’s total investment per year in research relevant to PDAC (pancreatic cancer), the amount is much greater than $105 million because many areas of study that are central to PDAC (pancreatic cancer) research—the KRAS signaling pathway (and its interaction with and activation of other pathways), genetic risk factors and somatic mutations, tumor suppressor genes, immune responses to solid tumors, diagnostic and screening technology development, combination therapeutic strategies including drug discovery and development—are shared with studies of other types of cancers and are supported by numerous NCI grants and contracts as well.

 

Research Resources:

Beyond grants, the NCI has many resources all of which are available to researchers working on PDAC (pancreatic cancer) and many other relevant cancers. Over 100 scientific resources are available to qualified scientists. The resource topics include: animals and animal models; drug and biological drug development, manufacturing, screening, and repositories; epidemiology and statistics; human and animal specimen collection and distribution; scientific computing; and family registries and cancer genetics (https://resresources.nci.nih.gov). Specific areas of interest to pancreatic cancer research are: The Cancer Genome Atlas (TCGA) program which generates comprehensive profiles of gene expression, epigenetic modifications, copy-number variation, and somatic mutations in tumors together with matched normal DNA sequence information and provides a platform for researchers to search, download, and analyze data sets generated by TCGA; the Early Detection Research Network (EDRN), a network of laboratories and centers (Biomarker Developmental Laboratories; Biomarker Reference Laboratories; Clinical Validation Centers; Data Management and Coordinating Center) whose goal is to accelerate the translation of biomarkers into clinical applications and to evaluate new ways of testing cancer in its earliest stages; the Clinical Proteomic Tumor Analysis Consortium (CPTAC) which systematically identifies proteins that derive from alterations in cancer genomes and related biological processes, and provide this data with accompanying assays and protocols to the public; the Mouse Models of Human Cancers Consortium (MMHCC) which derives and characterizes mouse models, and generates resources, information and innovative approaches to the application of mouse models in cancer research; the NCI Clinical Trials Network (NCTN) which conducts definitive, randomized, late phase clinical treatment trials and advanced imaging trials across a broad range of diseases and diverse patient populations as part of the NCI’s overall clinical research program for adults and children with cancer. The Specialized Programs of Research Excellence (SPOREs) is a grant program in translational research that uses a team science, multidisciplinary approach to focus on specific organ site cancers. There are currently three pancreatic cancer SPOREs and one gastrointestinal SPORE that has pancreatic cancer-related projects. An additional two SPOREs are supporting approaches to the targeting of KRAS. Each of these grants is required to have a biospecimen/pathology CORE (to collect, analyze, store, and annotate specimens) which in addition to supporting the research in the grant has the obligation to share specimens with the scientific community. SPOREs also provide opportunity for collaboration, including international collaboration, through the Developmental Research Program in each grant. Examples of SPORE research resources and projects related to pancreatic cancer can be found using these links: http://trp.cancer.gov/spores/pancreatic.htm; http://trp.cancer.gov/spores/gi.htm.

For investigators studying PDAC (pancreatic cancer), another resource is the International Cancer Research Partnership (ICRP). The ICRP, established in 2000, is an alliance of public and private cancer research funding organizations from around the world working together to enhance global collaboration and strategic coordination of research. Members who fund pancreatic cancer research include the NCI, Pancreatic cancer Action Network, Canadian Cancer Research Alliance, Dutch Cancer Society, National Pancreas Foundation, National Cancer Research Institute, American Institute for Cancer Research, American Cancer Society, and Institut National du Cancer. All of the partners code their research portfolios according to a Common Scientific Outline, a classification system that groups research into seven areas: biology; etiology; early detection, diagnosis, and prognosis; treatment; cancer control, survivorship, and outcomes research; and scientific model systems. The pooled data is incorporated into a shared database that researchers can search to identify potential collaborators and avoid duplication of efforts (https://www.icrpartnership.org).

 

Evaluation and Expansion of the Scientific Framework for PDAC (pancreatic cancer) Research

NCI’s research framework for PDAC (pancreatic cancer) was examined during a multidisciplinary workshop convened to develop a forward-looking scientific approach for this recalcitrant disease. The workshop report, Pancreas Cancer: Scanning the Horizon for Focused Interventions, was presented to and accepted by the NCI Clinical Trials and Translational Research Advisory Committee (CTAC) at the March 2013 meeting, and is available in Appendix 1 and on the internet at: http://deainfo.nci.nih.gov/advisory/ctac/workgroup/ctacsupmat.htm.

 

Research Initiatives Proposed:

Four initiatives to expand PDAC (pancreatic cancer) research were recommended by the workshop:

  1. Understanding the biological relationship between PDAC (pancreatic cancer) and diabetes mellitus
  2. Evaluating longitudinal screening protocols for biomarkers for early detection of PDAC (pancreatic cancer) and its precursors
  3. Studying new therapeutic strategies in immunotherapy
  4. Developing new treatment approaches that interfere with RAS oncogene-dependent signaling pathways

 

Relationships between PDAC (pancreatic cancer) and diabetes mellitus (DM)

Clinical and genetic epidemiological studies have identified an association between DM of recent diagnosis and a subsequent diagnosis of pancreatic cancer28. About half of all PDAC (pancreatic cancer) patients have DM at the time of diagnosis, and half of those patients have experienced the onset of DM within the prior 3 years. Yet, only 1% of recent-onset DM patients will develop PDAC (pancreatic cancer) within 3 years28. Progress in the early detection of PDAC (pancreatic cancer) will therefore require a more detailed understanding of the clinical and biological characteristics of the population of patients who subsequently develop or have undiagnosed PDAC (pancreatic cancer) in the setting of newly diagnosed diabetes. It will be essential to define specific risk factors to make screening efforts cost-effective by focusing on these individuals. It also will be important to understand whether other risk factors for the development of PDAC (pancreatic cancer) (such as exposure to tobacco smoke) interact with diabetes to increase the risk of PDAC (pancreatic cancer). This is especially true for individuals with type 3c diabetes (diabetes secondary to pancreatic diseases) with coexisting chronic pancreatitis, in whom the risk of PDAC (pancreatic cancer) is increased 30-fold. Research efforts should determine whether risk factors of sufficient specificity can be defined to justify a coordinated early detection program in these patient groups.

Screening protocols for biomarkers for early detection of PDAC (pancreatic cancer) and its precursors

The goal of early detection strategies is to identify patients with the earliest-stage pancreatic cancers, who have the best chance of cure, and those individuals who are at highest risk, i.e., individuals who have precursor lesions that are likely to evolve into PDAC (pancreatic cancer). Two groups of patients with precursor lesions, defined by pathologic or radiologic criteria, are those with type 3 highly dysplastic PanINs or cystic neoplasms of the pancreas–either IPMN or MCN. These patient populations overlap with the population of individuals who have germline mutations in specific genes that predispose to PDAC (pancreatic cancer) (such as BRCA2, LKB1, etc.) as well as families with multiple first-degree relatives who have developed PDAC (pancreatic cancer). Genetically-defined patient populations also frequently harbor high-grade PanINs or small mucinous cysts that serve as pathologic precursors to invasive pancreatic cancer47. However, estimating the true extent of these lesions in the entire population has proven difficult; thus, the major diagnostic challenge is to develop more accurate and sensitive methods of imaging and more accurate and sensitive methods to identify the molecular alterations that characterize these lesions to improve early detection. This research effort should evaluate longitudinal screening protocols for patients at high risk of developing PDAC (pancreatic cancer) because of their genetic background or the presence of mucinous pancreatic cysts. These screening protocols, especially those that could collect specimens from early lesions, fluid from cysts, circulating tumor cells, or DNA from serum may help in the development of new molecular or imaging biomarkers that could be used in the selection of patients for early surgical intervention.

Immunotherapy approaches

The intrinsic cellular heterogeneity and genetic instability48 of PDAC (pancreatic cancer)s as well as the lack of understanding of the complex interrelationships among tumor cells, stromal cells, and immune cells characteristic of this malignancy have contributed in the past to the slow progress in developing effective systemic therapies for this disease49. In addition, the dense desmoplastic reaction itself, with its extensive deposition of extracellular matrix, is thought to act as a physical barrier and a great challenge to therapeutic success. It has recently been shown in a PDAC (pancreatic cancer) GEMM that mutational activation of KRAS triggers the production, by PDAC (pancreatic cancer) precursor lesions, of the growth factor GM-CSF, which promotes the expansion of Gr-1+ CD11B+ myeloid cells as part of the inflammatory reaction. These immature myeloid cells (also known as myeloid suppressor cells) suppress CD8+ T cell antitumor immunity. Breakthroughs in targeting stromal cells, in reversing immunosuppression, and in the use of immune checkpoint blockade agents, vaccines, and T cell-based immunotherapies, alone or in combination, have created opportunities for progress against PDAC (pancreatic cancer).

RAS-specific therapeutics

Advanced PDAC (pancreatic cancer) is resistant to treatment with cytotoxic agents as well as the molecularly targeted drugs that have been tested to date. One of the reasons for this is the high frequency of an activating mutation in KRAS—the oncogenic driver of PDAC (pancreatic cancer)—which has been notoriously difficult to target with drugs. After more than 30 years of research into RAS and its role in pancreatic (and other) cancers, it has become evident that targeting this oncogene requires new approaches. These should include research efforts to develop new treatments employing recently discovered techniques in chemical biology supporting the discovery of molecules that interfere with RAS-oncogene-dependent signaling pathways. Since KRAS mutations are common in PDAC (pancreatic cancer) and many other malignancies, endeavors to target KRAS provide an opportunity to make inroads into establishing new therapies that might be widely applicable to the treatment of PDAC (pancreatic cancer) as well as other cancers.

 

Plans for Implementation of Recommended Initiatives

Coordinated Research Initiatives:

In response to the recommendations from the workshop, NCI has developed plans to pursue the four proposed research initiatives and has taken action on some of these. In general, the recommended research initiatives fall into one of four general categories: 1) developing a better scientific understanding at the molecular epidemiologic level of how specific predisposing factors, such as recently-developed diabetes or familial predisposition to PDAC (pancreatic cancer), lead to the onset of this disease; 2) enhancing research into the discovery of biomarkers to identify PDAC (pancreatic cancer) precursor lesions that might be amenable to early treatment; 3) utilizing recent advances in cancer immunology to develop new immunotherapies for PDAC (pancreatic cancer); and 4) pursuing new therapeutic approaches to mutant forms of the RAS oncogene that are present in the majority of patients with PDAC (pancreatic cancer).

Relationship between PDAC (pancreatic cancer) and diabetes mellitus

The workshop established that some patients with new-onset DM constitute a high to moderate risk group for PDAC (pancreatic cancer) and that some of these patients might already have early stage PDAC (pancreatic cancer) which might be amenable to resection and cure. The use of familial pancreatic cancer registries would be a starting point for studies and screening. Mining data from health maintenance organizations could be used to establish new cohorts for imaging studies. Additional annotations about obesity and smoking might refine the population for screening.

In June 2013, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the NCI, together with the Pancreatic cancer Action Network, sponsored a two-day interdisciplinary meeting: NIDDK-NCI Pancreatitis-Diabetes-Pancreatic cancer Workshop, as an initial step toward understanding the clinical and biological relationships between chronic pancreatitis (CP), PDAC (pancreatic cancer) and DM (http://www.niddk.nih.gov/news/events­calendar/Pages/niddknci-workshop-on-pancreatitisdiabetespancreatic-cancer.aspx). The purpose of the workshop was to explore the known and suspected mechanisms for the increased risk for PDAC (pancreatic cancer) associated with chronic pancreatitis (CP) and DM; to identify the prevalence of type 3c DM (T3cDM; diabetes associated with diseases of the pancreas) in the overall DM population; to assess strategies to differentiate T3cDM from Type 2 DM (T2DM); to review the effects of anti-diabetic therapy on the development of PDAC (pancreatic cancer); and to explore possible PDAC (pancreatic cancer) surveillance methods for T2DM and T3cDM patients. Sessions included: Overview of the Problem; Chronic Pancreatitis as a Risk Factor for PDAC (pancreatic cancer); Diabetes as a Risk Factor of PDAC (pancreatic cancer); Pancreatogenic (Type 3c) Diabetes; Genomic Associations of CP, DM, and PDAC (pancreatic cancer); and Surveillance of High-risk Populations and Early Detection of PDAC (pancreatic cancer). Participants defined high-priority strategies that need to be pursued in the areas of mechanisms, biomarkers, and refinement of risk. One important area that needs resolution is the controversy over whether relatively new diabetes drugs that are agonists for the glucagon-like peptide 1 (GLP-1) receptor (expressed in pancreatic duct cells) or inhibitors of dipeptidyl peptidase-4 (DPP-4) cause pancreatitis, development of PanINs, and PDAC (pancreatic cancer). Data on both sides of the argument were presented, but no consensus was established. Discussion also included the potential beneficial role of metformin in reducing or preventing PDAC (pancreatic cancer) recurrence56 .  Recommendations for next steps: The NCI/NIDDK workshop attendees recommended that the NCI and NIDDK publish the meeting proceedings and develop a funding opportunity announcement (FOA) for expanding research in all the areas considered critical.

Biomarkers for Early Detection of PDAC (pancreatic cancer) and Its Precursors

There is consensus that the discovery of biomarkers that can identify early lesions (PanINs 2 and 3, and mucinous pancreatic cysts) and perhaps serve as therapeutic targets is a critical goal in advancing progress in PDAC (pancreatic cancer) since diagnosis of pre-invasive or even small cancers can improve resectability, prognosis after resection, and survival. To date, there are no biomarkers or panels of biomarkers that are sensitive and specific enough for diagnosis of PDAC (pancreatic cancer) in its early stages. Cysts can be detected by current imaging techniques, but many cysts are benign and wholesale surgery is not recommended because of morbidity and cost considerations. One group of investigators has shown a significant difference between the expression and glycosylation of specific proteins in cysts with high malignant potential and cysts with low malignant potential, and has suggested that these molecules could serve as biomarkers for the diagnosis of high risk pancreatic cysts. Armed with new information about activated molecular pathways, technological advances in screening strategies and non-invasive imaging, investigators are now poised to discover novel methods of detecting early lesions59. Work is in progress in several laboratories on refining the standard assay for the carbohydrate antigen, CA19-9, by measuring CA19-9 on specific protein carriers; the pattern of expression on these carriers has been shown to discriminate PDAC (pancreatic cancer) from pancreatitis60. However, the ideal biomarker should also be able to detect pre-invasive cancers or precursor lesions. Proteomic techniques are also being used in to identify serum proteins and peptides that indicate premalignant PanINs. Many of the studies in early biomarkers for PDAC (pancreatic cancer) are collaborative and supported by cooperative agreements through EDRN. Other areas of investigation are the use of novel imaging techniques, miRNAs, circulating tumor cells, circulating DNA, autoantibodies, and methylated DNA as early detection biomarkers.

Recommendations for next steps:

For further progress in the development of early detection biomarkers, it will be essential to optimize screening protocols, to improve enrollment of high risk populations in screening studies, and, crucially, to demonstrate that screening can improve the outcome of patients. A potentially useful approach to enhancing screening research is to prospectively harvest and analyze tissue from patients with PanIN-2 and -3 lesions during resection, and from cyst fluid from those undergoing endoscopic ultrasound and fine needle aspiration. Through the issuance of a Program Announcement over the next twelve months, focusing on the development of novel methods to obtain and interrogate pancreatic tissues containing pre-neoplastic lesions, the NCI will actively stimulate studies in this area.

Immunotherapy

Recent advances in cellular and molecular immunology have led to a detailed understanding of the induction and regulation of the immune response to cancer, including the complex network of signaling and checkpoint pathways involved; to a comprehension of the dynamic processes involved in the interaction between tumor and the cells of its microenvironment, including the action of soluble mediators that aid or inhibit the immune response; and to the recognition that most human cancers have the potential to respond to immunomodulation therapy either as single agent therapy or in combination with other agents. Data provide evidence that many early-stage tumors induce an immune response, but an immunosuppressive environment that inhibits an anti-tumor response is often quickly established. Yet, promotion of T-cell­dependent antitumor immunity can result in tumor regressions in patients with metastatic pancreatic as well as other types of cancer21.

The availability of new immune response modifiers, including FDA-approved agents that can modify interactions between tumor cells and the surrounding stromal cells, provides opportunities to accelerate research in the development of effective pancreatic cancer immunotherapies. Genetically engineered immunocompetent mouse models of spontaneous pancreatic cancer that closely mimic the human disease, including the development of early lesions (i.e., PanINs and mucinous cystic neoplasms) and the generation of dense desmoplasia, have permitted more relevant ways to test new therapies than do transplantable tumor models64.

Much of the NCI-supported research in immunotherapy of pancreatic cancer has been in the area of therapeutic vaccines. It has been postulated that the best chance for these vaccines to have an anti-tumor impact on pancreatic cancer would be in the post-surgical (minimal disease) setting. The optimal strategy would be to create a vaccine against unique pancreatic tumor antigens/neoantigens that play key roles in cancer growth and progression. Although the NCI is funding investigators to discover, characterize, and validate such antigens, only a few have been discovered so far. Therefore, allogeneic whole cell vaccines that have been engineered to secrete

GM-CSF, a growth factor for dendritic cells, have been used in pre-clinical and clinical studies, predominantly. Current trials have added ipilimumab, an FDA-approved antagonistic monoclonal antibody against CTLA4, which is a T cell receptor that when it engages its ligands, CD80 and CD86, downregulates the immune response. The detection in paraffin-embedded pancreatic cancer specimens of PD-L1 (also known as B7­H1), another negative regulator of T cell responses, and the availability of antagonistic anti-PD­L1 monoclonal antibodies, have created further opportunities for combining vaccines with immune checkpoint inhibitors70.  A CD40 agonistic antibody, which stimulates antigen-presenting cells, has been tested in combination with gemcitabine in a clinical trial of pancreatic cancer patients and is being followed up with additional studies. Concomitant laboratory studies have demonstrated that this antibody drives both T cell-dependent and T cell-independent mechanisms of action and is thought, in pancreatic cancer, to cause stromal involution and re-education of tumor-associated (suppressive) macrophages.

An industry-sponsored series of studies that has now reached a Phase 3 trial is testing algenpantucel-L, an allogeneic whole cell pancreatic cancer vaccine that has been genetically modified, together with gemcitabine or gemcitabine plus 5-fluorouracil chemoradiation, in surgically resected pancreatic cancer patients [ClinicalTrials.gov identifier: NCT01072981.]73

In September 2013, the Center of Excellence in Immunology at the NCI’s intramural Center for Cancer Research sponsored a two-day conference on “Inflammation, Microbiota, and Cancer.” This conference discussed many aspects of cell-cell and cell-mediator interactions that are important to immunotherapy of pancreatic cancer.

Examples of NCI funded projects with high relevance to the immunotherapy of pancreatic cancer can be found using the following link: http://tiny.cc/fngu7w.

Recommendations for next steps: Progress in pancreatic cancer immunotherapy will include not only the support of grants dealing with the discovery and validation of new immunotherapy targets, and the rational combination of immune modifiers in preclinical and clinical studies, but the production of immune-modulatory molecules (such as anti-CD40) at the NCI’s Frederick National Laboratory for Cancer Research (FNLCR) to facilitate the initiation of early phase PDAC (pancreatic cancer) trials in the area of immunotherapy. For these clinical studies, the Cancer Immunotherapy Trials Network (CITN), which employs the collective expertise of expert academic immunologists together with the NCI, and foundation and industrial partners, will design and conduct cancer therapy trials with the most promising immunotherapy agents in PDAC (pancreatic cancer) patients.

RAS-Specific Therapeutics

Many common cancers are driven by mutant forms of RAS, including 95% of PDAC (pancreatic cancer), 45% of colorectal cancers, and 35% of lung adenocarcinomas. Although there have been many attempts at targeting cancer cells driven by KRAS, successful strategies so far have been elusive. Recent discoveries provide opportunities to make progress on this front. These include new information on signaling pathways and complexes based on recent advances in cell biology, protein engineering, the use of RNA interference for target identification in synthetic lethality screens, technological advances in conducting structural analyses, and the generation of genetically engineered mouse models that are more relevant to the human disease74.

NCI has mounted a large-scale program on RAS at the FNLCR, an HHS Federally Funded Research and Development Center that provides unique capabilities, resources, and approaches to conduct research and development, such as expertise in basic research, applied research and development capacity, clinical research including correlative studies, Good Manufacturing Practice (cGMP), and animal model facilities and experience.

In early 2013, a series of meetings were held with experts in the RAS field to discuss appropriate projects to pursue. Five projects were defined as having high priority75:

Pursuing allele specific compounds for those RAS alleles most prevalent in human cancer (e.g., KRAS G12D and G12V in pancreatic cancer)

  1. Developing KRAS selective binding compounds for KRAS ablation without allele specificity
  2. Developing imaging methods and screens to identify and disrupt KRAS complexes in cells and to monitor their disruption
  3. Mapping the surface of KRAS cancer cells and identifying epitopes that could be targeted by immunotherapy and proteins that could be targeted for drug delivery by nanoparticles
  4. Developing and conducting next-generation synthetic lethality screens and engineering mice to facilitate these screens

The first two projects involve structural and biological approaches to attack RAS directly. The third project, disrupting KRAS complexes within cells, presents new opportunities for drug discovery. The fourth project will define the landscape of proteins on the surface membranes of mutant KRAS cells and facilitate the development of direct antibody-mediated interventions, immune-based therapies—such as adoptive transfer of T cells engineered to attack tumor antigens, and nanoparticle-mediated drug delivery. The fifth project will conduct synthetic lethality screens, including those in 3D cell cultures and animals, in order to discover combinations of proteins that mutant KRAS cells require for survival. Results from this project could lead to the development of new combinations of targeted therapies. Studies will also be performed in other areas of RAS biology, related to both HRAS and NRAS—variants that are relevant to other forms of human cancer. However, much of the entire effort will be specifically directed at KRAS, the form of mutant RAS found in approximately 95% of PDAC (pancreatic cancer) patients.

These five projects, which were unanimously approved by the NCI Board of Scientific Advisors and the National Cancer Advisory Board at their joint meeting in June 2013, will be conducted within a “RAS community,” by a hub and spoke model, with scientific leaders, core facilities and critical technologies and materials provided by the Advanced Technologies Research Facility at the FNLCR “hub”; and a distributed research effort by a community of investigators at academic institutions, pharmaceutical and biotechnical companies, and the NCI intramural research program as the “spokes.”

Recommendations for next steps:

Progress, as the project relates to advances in pancreatic cancer, will be measured by periodic reports, publications, and presentations. Some of these will report on the creation of the tools necessary to support the activities of the five projects. These include methods for solving the structures of mutant proteins complexed with relevant effectors and regulators; determining the significance of other types of modifications to RAS proteins, including acetylation and ubiquitination; identifying compounds that disrupt RAS dimers or other aspects of RAS superstructures; developing a comprehensive map of surface proteins on specific RAS cancers; and developing synthetic lethal screens in vitro and in vivo. Other reports will cover the generation and validation of data, using these tools, to target mutant RAS cancer cells, and the application of the new methods to the treatment of PDAC (pancreatic cancer) in pre-clinical and clinical trials.

 

Oversight and Benchmarks for Progress

The NCI has regularly reviewed its portfolio of PDAC (pancreatic cancer) research, at least since 2000, when the NCI convened the Pancreatic cancer Progress Review Group (PCPRG), a multidisciplinary committee of scientists, clinicians, and advocates; the PCPRG reviewed the field of PDAC (pancreatic cancer) research and made prioritized recommendations concerning promising directions for future scientific investment in this disease [National Cancer Institute. Pancreatic cancer: An Agenda for Action. Report of the Pancreatic cancer Progress Review Group. NIH Publication No. 01­4940. Bethesda (MD): NCI; 2001. http://planning.cancer.gov/library/2001pancreatic.pdf]. This effort was followed by the development of a strategic plan to enhance PDAC (pancreatic cancer) research [National Cancer Institute. Strategic Plan for Addressing the Recommendations of the Pancreatic cancer Progress Review Group. Bethesda (MD): NCI, 2002. http://planning.cancer.gov/library/pancreatic.pdf]. The clinical trials portfolio in the area of PDAC (pancreatic cancer) was examined during a Clinical Trials Planning meeting of NCI’s Pancreatic cancer Task Force (2008); this workshop defined future directions for NCI-supported clinical trials in pancreatic cancer based on input from academic, industry, community, and advocacy experts76.

To assess the ongoing investment of the NCI in PDAC (pancreatic cancer) research, the Pancreatic cancer Action Planning Group (PCAPG) was formed in 2010; its recommendations and the subsequent implementation plan established the current framework for NCI’s PDAC (pancreatic cancer) research program [National Cancer Institute. Pancreatic cancer: A Summary of NCI’s Portfolio and Highlights of Recent Research Progress. Bethesda (MD): NCI; 2010. http://www.cancer.gov/researchandfunding/reports/pancreatic-research-progress.pdf]. This report was followed by an “action plan” in 2011 [National Cancer Institute. National Cancer Institute Investment in Pancreatic cancer Research: Action Plan for Fiscal Year 2011]. http://www.cancer.gov/researchandfunding/reports/pancreatic-action-plan.pdf]. The NCI’s PCAPG continues to meet on a regular basis; most recently, it was responsible for developing the joint NCI/NIDDK workshop on the role of diabetes mellitus in PDAC (pancreatic cancer) described in a preceding section of this report. The PCAPG will continue to monitor the progress of the initiatives for expanded research proposed at the Scanning the Horizon workshop.

Conclusion

The workshop, Pancreatic cancer: Scanning the Horizon for Focused Interventions, provided the NCI with expert advice regarding how to extend its existing extensive repertoire of PDAC (pancreatic cancer) research, with the goal of making further progress against PDAC (pancreatic cancer), a disease whose incidence continues to slowly increase, and for which no breakthroughs leading to improved patient survival have occurred. The workshop recommended expanding research in specific areas in ways that could advance the field and open up possibilities for better outcomes.

The NCI has made a significant investment in pancreatic cancer research and will continue to support research in the field, particularly in the four areas that the workshop attendees designated as of high priority for expansion:

 Understanding the relationship between PDAC (pancreatic cancer) and diabetes

 Evaluating longitudinal screening protocols for biomarkers for early detection of PDAC (pancreatic cancer) and its precursors

 Studying new therapeutic strategies in immunotherapy

 Developing new treatment approaches that interfere with RAS-oncogene-dependent signaling pathways

Reports to the Clinical Trials and Translational Research Advisory Committee (CTAC) at regular intervals will inform the public of progress in this difficult disease and fulfill a requirement of the Recalcitrant Cancer Research Act. To implement the specific recommendations proposed in this report:

 The NCI will continue to work with NIDDK to develop new funding opportunities for studying the diabetes—PDAC (pancreatic cancer) connection

 The NCI’s Cancer Therapy Evaluation Program will facilitate testing combinations of molecularly targeted drugs and biological agents from different companies in a broad range of clinical trials for patients with PDAC (pancreatic cancer) that include immunotherapeutic studies

 The NCI will oversee funded grant programs supporting PDAC (pancreatic cancer) research and monitor progress in the priority areas, including the development of new biomarkers for patients with mucinous cystic diseases of the pancreas and individuals with a familial predisposition to PDAC (pancreatic cancer)

 The NCI will continue its commitment of considerable resources to the RAS project, which includes a five-pronged approach to tackling an oncogene highly relevant to PDAC (pancreatic cancer)

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