Yesterday, European researchers and those from MD Anderson Cancer Center/ University of Texas in Houston published an article in the prestigious journal, Nature, which carries the possibility of being a game-changer in the earlier diagnosis and consequent treatment of pancreatic cancer (ductal adenocarcinoma of the pancreas). It is difficult to overstate the potential for significant positive effects of these findings in the treatment of pancreatic cancer should the fascinating results bear up under replication and scrutiny.
The results of the presented research identify a diagnostic marker for pancreatic cancer that exists as an exosome containing a specific protein/saccharide complex that is attached to the outside wall of its spherical structure as it courses its way through human fluids (including serum) in humans with pancreatic cancer. This proteoglycan marker is known as glypican-1, a cell surface heparan sulfate.
The presence of these “glypican-1 exosomes” in human serum demonstrated 100% sensitivity and 100% specificity as to the presence of pancreatic cancer in individuals. These remarkable findings were seen in late and early pancreatic cancer, and extended even to the putative precursor: intraductal papillary mucinous neoplasms (IPMNs).
Here at our Pancreatica blog we have been intrigued by “exosomes” in the interest of the earlier diagnosis of pancreatic cancer for a while [Here] and [Here]. Exosomes, first discovered in the 1980s, are round lipid structures containing intracellular bits of RNA, DNA, parts of cellular proteins, and other substances. In a process that is not fully understood (and which may not be uniform) exosomes appear to be formed by the pinching off or budding of a cell wall. The resultant small structure has a typical diameter of approximately 30 to 100 nanometers, and essentially “floats” through the fluids of the mammalian body. Exosomes are found essentially in all fluids including, for example, saliva. It has been thought that the function of exosomes may include extracellular communication, waste disposal, unknown immune response or interaction, and tumor invasion. An exosome appears to be able to transfer its contents from one cell to another, even at a distance.
The fifteen named authors of this study are researchers from medical institutions in Dresden, Germany; Porto, Portugal; Orviedo, Spain; Madrid, Spain; and Houston, Texas. The corresponding author is Raghu Kalluri, MD, PhD at the Department of Cancer Biology, Metastasis Research Center, University of Texas/ MD Anderson Cancer Center, Houston, Texas 77054, USA. The 29-page article was published on June 24, 2015 in the journal Nature.
The research was done with cell lines, mice, and in human subjects. Other findings of this work demonstrate that the level of the concentration of the glypican-1 exosomes is correlated with overall pancreatic cancer tumor burden, and with the survival duration of pre-operative and post-operative patients. Glypican-1 exosomes reliably demonstrate KRAS mutation (common in pancreatic cancer, and thought to be an oncogenic driver) in messenger-RNA found in the structures. Glypican-1 exosomes appear to be a more valid biomarker than CA 19-9 for the detection of pancreatic cancer. In genetically-engineered mice models, glypican-1 exosomes are detectable in serum before pancreatic cancer tumors show anatomically by MRI. If the findings hold, the increased specificity of the glypican-1 exosomes avoids the pitfalls of confusion with pancreatitis or other pancreatic disorders, as is now the case with a number of biomarkers including CA 19-9.
The researchers additionally found increased glypican-1 exosome levels (but not as definitive) in breast cancer. And they note that glypican-1 could serve as a pan-specific marker of cancer exosomes.
The pancreas related patients and healthy controls were all from Germany: the University Hospital of Heidelberg and the University Hospital of Dresden. These included 246 patients with pancreatic cancer (pancreatic ductal adenocarcinoma), 24 patients with pancreatitis, 8 patients with a benign serous cystadenoma, 5 patients with diagnosed IPMN, and 20 healthy controls. The University of Texas / MD Anderson Cancer Center contributed data from 32 women with breast cancer.
In passing, we note that heparan sulfate is a member of the glycosaminoglycan family of carbohydrates and is very closely related in structure to heparin, the anticoagulant in common use. Both consist of a variably sulfated repeating disaccharide unit.
These research findings are remarkable. If replicable and verified, they will be a major breakthrough for the early diagnosis of pancreatic cancer. This could lead to potentially curative surgery for a major portion of those found to have pancreatic cancer, which now is available only to about 15% of patients upon diagnosis. We eagerly await confirmation.
Dale O’Brien, MD
In a certain way, the initial treatment considerations for local and advanced pancreatic cancer (ductal adenocarcinoma of the pancreas) are not as complex as those of locally advanced pancreatic cancer. Local cancer is typically treated with surgical resection – some version of the Whipple Procedure. And the treatment of advanced pancreatic cancer is generally some form of chemotherapy regimen. The “standard” for non-operable locally advanced pancreatic cancer has been chemoradiation. And an active area of inquiry has been the best treatment option for borderline resectable locally advanced pancreatic cancer, or perhaps unresectable locally advanced pancreatic cancer as based on vascular encasement or abutment by the tumor.
Now comes a study by Allendorf and his surgical colleagues from Columbia University in New York City that examines outcomes for over five hundred patients who received the pancreaticoduodenectomy (Whipple) surgery for locally advanced pancreatic cancer at Columbia from the years 1992 to 2011. The authors’ review of patient records treated at their institution initially found 643 patients with locally advanced disease who had appeared to fit surgical criteria. At surgery, only 506 of these patients were found by the operating surgeon to merit surgery. Published in the May 2014 edition of the World Journal of Surgery, the authors looked at survival duration in terms of neoadjuvant status as well as whether vascular resection was done.
The authors found that although neoadjuvant therapy appeared associated with an increase in operative mortality (7% vs. 3%), that more neoadjuvant pancreatic cancer patients underwent vascular resection, and that neoadjuvant therapy status significantly increased overall survival (as compared to no receipt of neoadjuvant treatment) at a p < 0.5 confidence level of 27.3months versus 19.7 months.
It tentatively appears that certain patients with apparently unresectable locally advanced pancreatic cancer – as determined by traditional criteria – may gain a potentially improved survival advantage if they respond to neoadjuvant therapy such that they then become candidates for pancreatic surgery, including vascular resection.
This is an interesting and fine study that on one hand further complicates the treatment landscape for locally advanced pancreatic cancer, but offers potential improved results for many.
Dale O’Brien, MD
Dutch and primarily other European researchers are about to begin a human clinical trial involving a regimen of two relatively new targeted therapies (afatinib plus selumetinib) for the treatment of pancreatic cancer (ductal adenocarcinoma of the pancreas). Afatinib is known as Gilotrif in the U.S., and is produced by the family-owned global but German-headquartered Boehringer Ingelheim Pharmaceuticals firm. Selumetinib is produced by the AstraZeneca firm (AZ); it is currently in the Phase III SELECT-1 clinical trial in combination with docetaxel for the second-line treatment of KRAS positive non-small cell lung cancer. AZ is partnering with Roche Molecular Systems to develop a test marker to help identify those patients who are most likely to respond to selumetinib.
The lead institution for the upcoming clinical trial involving pancreatic cancer will be the Antoni van Leeuwenhoek Hospital in Amsterdam. The work is based on earlier study by Bernards, Sun and other researchers who laid the predicate for this research in a recently published medical article on March 17, 2014 in the journal Cell Reports about the effects of this combination regimen in overcoming Kras resistant lung and colon cancer. The coming human clinical trial will also include lung and colon cancer, as well as pancreatic cancer.
The mutated ras oncogene is found in approximately 90% of cases of pancreatic cancer (pancreatic adenocarcinoma), and generally in about 20 – 30% of human cancer. These cancers tend to be ones that are particularly difficult to treat – with a tendency to poor outcome. In fact, one of the four specific initiatives proposed by the recent Scientific Framework for Pancreatic Ductal Adenocarcinoma of the U.S. National Cancer Institute is: “Developing new treatment approaches [for pancreatic cancer] that interfere with RAS oncogene-dependent signaling pathways.”
The recent study by Bernards et al. on Kras mutant colon and lung cancer found that suppression of the tyrosine kinase receptor ERBB3 had the effect of sensitizing these tumor cells to MEK inhibitors. Afatinib is a tyrosine kinase receptor inhibitor that not only affects epidermal growth factor receptor (EGFR – as does erlotinib -Tarceva), but also acts in a wider manner in these regards. Afatinib received U.S. FDA approval on July 12, 2013 for the treatment of metastatic non-small cell lung cancer which has EGFR exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test. Selumetinib blocks the enzyme MAPK kinase (MEK) that is just “downstream” from the BRAF gene and which is also involved in the Kras gene signaling pathways.
In the recent published study, the authors found that the combination of these targeted therapies acted synergistically in promoting cell death in Kras resistant lung and colon cancer cells, AND in significantly reducing tumor growth (to about zero growth over the 4-week study period) in referent mice models. It is easy to see why the authors have now added pancreatic cancer to the study.
Thus, the researchers have presented biological plausibility of the regimen in mutated Kras tumors and have established a basis for possible preliminary efficacy in pre-clinical studies in regard to pancreatic cancer. And so the process of human testing begins. It will be of some interest to see if the efficacy holds in human subjects, and what the tolerability profile will reveal. And the effect specifically on pancreatic cancer. This is interesting and promising work.
Dale O’Brien, MD