Leaders in Pharmaceutical Business Intelligence (LPBI) Group

Author: Tilda Barliya PhD

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Pancreatic cancer has been previously addressed here in our blog (I-IX) but a recent diagnosis of a colleague urged me to go back to the basics and search for more answers and updates hoping it would offer some peace.

Pancreatic cancer is the 4th leading cause of death in the united states with only 3% rate for 5-year survival rate (1). Due to lack of symptoms and limitation in diagnostic methods, patients are mostly diagnosed at mush advanced stages. When reach these stages, patients start to show symptoms of weight loss, abdominal pain, jaundice, by than, the cancer has already spread.

Several treatment options are available in which surgical resection (for the 15%-20% that are eligible for it) increase the 5-year survival rate by up to 20% , and that’s mainly because the cancer comes back about 85 percent of the time (1,2). These statistics are very hard to comprehend, especially with the progress been made in other types of cancer.

So Why pancreatic cancer is so deadly?

The pancreas is a highly vascularized 6 inch dual-function gland that plays a major role in the body. It secretes digestive enzymes and hormones (i.e; insulin, glucagon, somatostatin and pancreatic polypeptide) which assist in the digestion of fats and the absorption of nutrients. These enzymes help further digest carbohydrates, proteins and lipids in the chyme.

It is postulated that a tumor starts to overcome  the functionally of the pancreas;  causing reduction of important hormones (insulin) and enzymes (digestive enzymes) production thus impacting the overall ability of the body to absorb nutrients and get energy coins thus affecting  the overall performance of the body. Several studies were conducted to evaluate the connection between dietary factors and induction of pancreatic cancer, however no direct correlation was observed (11, 12)

More so, the pancreas is located at the junction of several organs; liver, gall bladder and intestines,  thus enabling metastatic cells to harbor multiple vital organ. Most patients die for liver failure due to liver metastases.

These factors; late- diagnosis, reduction in overall body function and failure of vital organs (such as the liver due to metastasis), cause the aggressive and fast death of these panvreatic patients.

A growing number of studies have identified common mutational profiles in simultaneous lesions, providing supportive evidence of the relationship between pancreatic intraepithelial neoplasia (PanINs) and the pathogenesis of pancreatic adenocarcinoma. Nabeel Bardeesy and Ronald A. DePinho summarized this data in Figure and table inserted herein. Intriguingly, there seems to be an ordered series of mutational events in association with specific neoplastic stages (1,4).

The combination of these multiple mutations render pancreatic cancer cells resistant to current chemo and radiotherapy. More so, known pancreatic cancer antigens have generated relatively weak immune responses due to these combined mutagenesis (5, 16). These crucial somatic genetic mutations can generate pancreatic cancer proteins that are essentially altered self proteins

Therefore, in order to design a good  immunotherapeutic approach one must incorporate at least one agent against a pancreatic cancer target as well as one or more agents that will modify both local and systemic mechanisms of pancreatic-cancer-induced.

Another important element that needs to be taken into consideration are the immunological checkpoints. These checkpoints serve two  purposes:

1. To help generate and maintain self-tolerance, by eliminating T cells that are specific for self-antigens.
2. To restrain the amplitude of normal T-cell responses so that they do not ‘overshoot’ in their natural response to foreign pathogens

The prototypical immunological checkpoint is mediated by the cytotoxic-T-lymphocyte-associated protein 4 (CTLA4) counter regulatory receptor that is expressed by T cells when they become activated (6).  CTLA4 binds two B7 FAMILY members on the surface APCs — B7.1 (also known as CD80) and B7.2 (also known as CD86): with roughly 20-fold higher affinity than the T-cell surface protein CD28 binds these molecules. CD28 is a co-stimulatory receptor that is constitutively expressed on naive T cells. Because of its higher affinity, CTLA4 out-competes CD28 for B7.1/B7.2 binding, resulting in the downmodulation of T-cell responses (7). Monoclonal antibodies that downregulate B7-H1 and B7-H4 are currently in clinical development. This is just one example of the potential use of targeted therapy for use in clinical trials.

Dan Laheru* and Elizabeth M. Jaffee have summarized the immunotherapy clinical trials  back in 2005:

Herein you can read about the latest summary of the NCI portfolio on Pancreatic cancer and research highlights : http://www.cancer.gov/researchandfunding/reports/pancreatic-research-progress.pdf

Here’s their recommendation for future plans for clinical trials:

• Perform well-designed Phase II studies to help define strategies likely to succeed in a Phase III setting.
• Adopt consistent entry and evaluation criteria for Phase II trials.
• Conduct high-priority Phase III trials as intergroup trials and include scientifically appropriate biorepositories.
• Conduct trials on rational combinations of targeted agents and develop predictive biomarkers to assist in patient selection.
• Explore use of immune therapies, particularly among those with earlier stage disease.
• Share trial outcomes, including those of trials with negative results.

According to the NCI clinical trial results from two phase III clinical trials, the targeted therapies sunitinib (Sutent®) and everolimus (Afinitor®) increased the length of time patients with pancreatic neuroendocrine tumors (panNET) survived without the disease progressing. And, in the sunitinib trial, patients who received the drug also had better overall survival. The findings were published February 9, 2011, in the New England Journal of Medicine (NEJM). Although neuroadenoma is rare and presents only 2% of all pancreatic cancer, no effective treatment was available, now these results may offer some hope (9).

More so, a four-drug chemotherapy regimen has produced the longest improvement in survival ever seen in a phase III clinical trial of patients with metastatic pancreatic cancer, one of the deadliest types of cancer (10). Patients who received the regimen, called FOLFIRINOX, lived approximately 4 months longer than patients treated with the current standard of care, gemcitabine (11.1 months compared with 6.8 months).

In summary:

Remarkable progress has been made in understanding the  genetics and development biology pancreatic cancer have offered new potential targets for therapy. ” The availability of powerful new technologies and continued contributions of investigators in many related disciplines provides a measure of optimism towards future progress in treating this disease (1)”. Latest results of clinical trials may also shade some hope for patients suffering from this horrible disease.

On a personal note, I hope these new opportunities and clinical trials will offer another avenue to my colleague……

REFERENCES

1. Nabeel Bardeesy and Ronald A.DePinho. Pancreatic cancer biology and genetics. Nature Cancer reviews 2002, 2: 897-909. http://www.nature.com/nrc/journal/v2/n12/full/nrc949.html

2. Melinda Wenner. What makes pancreatic cancer so deadly. Scientific American 2008. http://www.scientificamerican.com/article.cfm?id=experts-pancreatic-cancer-gene-upshaw

3. Pancreas. Wikipedia. http://en.wikipedia.org/wiki/Pancreas

4. Jaffee, E. M., Hruban, R. H., Canto, M. & Kern, S.E. Focus on pancreas cancer. Cancer Cell 2, 25–28 (2002). http://www.sciencedirect.com/science/article/pii/S1535610802000934

5.  Dan Laheru* and Elizabeth M. Jaffee. Immunotherapy for pancreatic cancer – science driving clinical progress.  Nature Reviews: Cancer. 2005. 5: 459-467. http://www.nature.com/nrc/journal/v5/n6/full/nrc1630.html

6. Coyle, A. J. & Gutierrez-Ramos, J. C. The expanding B7 superfamily: increasing complexity in co-stimulatory signals regulating T cell function. Nature Immunol 2001. 2, 203–209. http://www.nature.com/ni/journal/v2/n3/full/ni0301_203.html

7.  Walunas, T. L., Bakker, C. Y. & Bluestone, J. A. CTLA-4 ligation blocks CD28-dependent T cell activation. J. Exp. Med 1996. 183, 2541–2550. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2192609/

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2192609/pdf/je18362541.pdf

8. Pancreatic Cancer: A summary of NCI’s portfolio and highlights of recent research progress 2010. http://www.cancer.gov/researchandfunding/reports/pancreatic-research-progress.pdf

9. NCI bulletin: Targeted Therapies May Be Effective Against Rare Pancreatic Cancer. http://www.cancer.gov/clinicaltrials/results/summary/2011/panNET-Therapy0411

10. NCI bulletin: Chemotherapy Regimen Extends Survival in Advanced Pancreatic Cancer Patients http://www.cancer.gov/clinicaltrials/results/summary/2011/pancreatic-chemo0611

11. Nilsen TI, Vatten LJ. A prospective study of lifestyle factors and the risk of pancreatic cancer in NordTrondelag, Norway. Cancer Causes Control 2000;11:645-52. http://www.ncbi.nlm.nih.gov/pubmed/10977109

12. Marshall JR, Freudenheim J. Alcohol. In: Schottenfeld D, Fraumeni JF Jr., eds. Cancer Epidemiology and  Prevention, 3rd ed. New York: Oxford University Press, 2006. P. 243-58. http://www.oxfordscholarship.com/view/10.1093/acprof:oso/9780195149616.001.0001/acprof-9780195149616

13. Alison P. Klein. Identifying people at a high risk of developing pancreatic cancer. Nature Reviews Cancer 2012, 13: 66-74. http://www.nature.com/nrc/journal/v13/n1/full/nrc3420.html

14. John P. Morris, Sam C. Wang & Matthias Hebrok. KRAS, Hedgehog, Wnt and the twisted developmental biology of pancreatic ductal adenocarcinoma.Nature Reviews Cancer 2012. 10:683-695.  http://www.nature.com/nrc/journal/v10/n10/full/nrc2899.html

15. Patrick Goymer. Imaging: Early detection for pancreatic cancer. Nature Reviews Cancer 2008, 8: 408-409. http://www.nature.com/nrc/journal/v8/n6/full/nrc2407.html

16. Koido S, Homma S, Takahara A, Namiki Y, Tsukinaga S, Mitobe J, Odahara S, Yukawa T, Matsudaira H, Nagatsuma K, Uchiyama K, Satoh K, Ito M, Komita H, Arakawa H, Ohkusa T, Gong J, Tajiri H. Current Immunotherapeutic Approaches in Pancreatic Cancer, Clin Dev Immunol. 2011;2011:267539. http://www.hindawi.com/journals/cdi/2011/267539/

Other related articles on this open Access Online Scientific Journal, include the following:

I. Pancreatic cancer genomes: Axon guidance pathway genes – aberrations revealed.

Aviva Lev-Ari, PhD, RN, 10/24/2012

http://pharmaceuticalintelligence.com/2012/10/24/pancreatic-cancer-genomes-axon-guidance-pathway-genes-aberrations-revealed/

II. Biomarker tool development for Early Diagnosis of Pancreatic Cancer: Van Andel Institute and Emory University.

Aviva Lev-Ari PhD,RN, 10/24/2012

http://pharmaceuticalintelligence.com/2012/10/24/biomarker-tool-development-for-early-diagnosis-of-pancreatic-cancer-van-andel-institute-and-emory-university/

III. Personalized Pancreatic Cancer Treatment Option.

Aviva Lev-Ari PhD, RN, 10/16/2012

http://pharmaceuticalintelligence.com/2012/10/16/personalized-pancreatic-cancer-treatment-option/

IV. Battle of Steve Jobs and Ralph Steinman with Pancreatic cancer: How we lost.

Ritu Saxena PhD, 5/21/2012

http://pharmaceuticalintelligence.com/2012/05/21/battle-of-steve-jobs-and-ralph-steinman-with-pancreatic-cancer-how-we-lost/

V.  Early Biomarker for Pancreatic Cancer Identified.

Prabodh Kandala, PhD, 5/17/2012

http://pharmaceuticalintelligence.com/2012/05/17/early-biomarker-for-pancreatic-cancer-identified/

VI. Usp9x: Promising therapeutic target for pancreatic cancer.

Ritu Saxen PhD, 5/14/2012

http://pharmaceuticalintelligence.com/2012/05/14/promising-therapeutic-target-discovered-for-pancreatic-cancer/

VII. Issues in Personalized Medicine in Cancer: Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing.

Stephen J. Williams, PhD, 10/4/2013

http://pharmaceuticalintelligence.com/2013/04/10/issues-in-personalized-medicine-in-cancer-intratumor-heterogeneity-and-branched-evolution-revealed-by-multiregion-sequencing/

VIII. In Focus: Targeting of Cancer Stem Cells.

Ritu Saxena, PhD, 3/27/2013

http://pharmaceuticalintelligence.com/2013/03/27/in-focus-targeting-of-cancer-stem-cells/

IIX. New Ecosystem of Cancer Research: Cross Institutional Team Science.

Aviva Lev-Ari. PhD, RN, 3/24/2013

http://pharmaceuticalintelligence.com/2013/03/24/new-ecosystem-of-cancer-research-cross-institutional-team-science/

IX. In Focus: Identity of Cancer Stem Cells.

Ritu Saxena, PhD, 3/22/2013

http://pharmaceuticalintelligence.com/2013/03/22/in-focus-identity-of-cancer-stem-cells/