Helping Win Steve Jobs' Pancreatic Cancer Fight For All of US Because iPads Are Not the Only Things That Matter

Yesterday, Steve Jobs once again returned to the world stage to introduce Apple's new iPad2 and once again the spotlight was also put on his ongoing battle with pancreatic cancer. 
Over a year ago, the death of Patrick Swayze in Sept 2009 brought pancreatic cancer into national consciousness (diagnosed at Stage IV in March 2008, died Sept. 2009.)  Since (and even before) then other public figures have battled this terrifying disease, including U.S. Supreme Court Justice Ruth Bader Ginsburg (diagnosed Feb 2009) and Steve Jobs the cofounder of Apple (diagnosed 2003).  Steve Jobs fortunately has a rare but treatable form of pancreatic cancer, neuroendocrine cancer or islet cell tumors.  These several public faces remind us, how overwhelmingly low the odds are in the battle against pancreatic cancer; of every ten patients diagnosed with pancreatic cancer, eight will not survive past one to two years.

Finally, turning the tables (or the house) on metastatic pancreatic cancer

Two very important advances were reported last month in the February issue of New England Journal of Medicine.  Two drugs, mTOR inhibitor everolimus (Afinitor, Novartis) and  the multi-receptor tyrosine kinase inhibitor sunitinib (Sutent, Pfizer) prolonged progression-free survival (PFS) in patients with metastatic pancreatic neuroendocrine tumors in Phase III trials. (news: read here, here, here)

• In the everolimus trial (the RADIANT-3 study) of 410 patients, everolimus prolonged progression-free survival which was 11.0 months, compared to 4.6 in placebo group.
• Sunitinib phase 3 study had 171 patients; the median progression-free survival was 11.4 months, compared to 5.5 months in the placebo group.

• In addition, several ongoing FOLFIRINOX trials also have the potential to radically improve the prognosis of metastic pancreatic cancer patients.  FOLFIRINOX is a chemo‐cocktail that combines FOLFIRI with oxaliplatin.

More tools, options and strategies to fight pancreatic cancer

• Mastinib, a multi-recptor tyrosine kinase (just like sunitinib) from AB Bioscience of Paris is in Phase III trials. [read here]  Mastinib inhibits cKIT, SCFR, PDGFR, FGF3 and FAK.
• BioSante Pharmaceuticals, Inc. of Lincolnshire, Illinois, (NASDAQ: BPAX) is testing GVAX Pancreas Vaccine for the treatment of pancreatic cancer. [...] A phase II study reported in the February 2011 issue of Annals of Surgery, showed that BioSante’s Pancreas Cancer Vaccine increased the median survival of resected pancreatic cancer patients from 15 to 20 months to 24.8 months, an increase of more than 25 percent. [...]
• Clavis Pharma (OSE: CLAVIS) of Norway is testing CP-4126, a novel, patented, lipid-conjugated derivative of the anti-cancer drug gemcitabine, in advanced, metastatic pancreatic cancer Phase II trial.   CP-4126 is absorbed by cancer cells independent of hENT1 levels.  hENT1 mediates gemcitabine entry; thus, CP-4126 may benefit patients with no or low hENT1 expression or overcome potential gemcitabine-resistance due to hENT1 mutations. [...]
• CureFAKtor Pharmaceuticals, LLC, of Buffalo, NY is working on Focal Adhesion Kinase (FAK) inhibitors for cancer.  Their lead compound, CFAK-C4 in development for the treatment of pancreatic cancer, was granted Orphan Drug Designation by the FDA.  Phase I trials are planned.  FAK mediates signaling between tumor cells and extracellular matrix; it also has a role in chemo or radioresistance of tumors. [...]
• Immunomedics, Inc. of New Jersey (Nasdaq:IMMU), is testing its proprietary antibody, clivatuzumab tetraxetan, labeled with yttrium-90 (Y-90) plus low-dose gemcitabine in a Phase II trial.  Clivatuzumab or hPAM4 is a humanized monoclonal antibody targeting a mucin antigen expressed in most pancreatic cancers, but not pancreatitis, normal pancreas or most other normal tissues.
• Infinity Pharmaceuticals, Inc. of Cambridge, Mass., (Nasdaq:INFI) initiated Phase 2 portion of the trial of IPI-926 in combination with gemcitabine in patients with previously untreated, metastatic, pancreatic cancer in Feb 2011.  IPI-926 is an oral small-molecule inhibitor of Smoothened, a key component of the Hedgehog pathway.[..., ..., ...]  The drug is being developed together with Purdue Pharmaceutical Products LP of Stamford, Conn., and Mundipharma International Corporation Ltd. of the UK.
•  Oncolytics Biotech Inc. of Calgary (TSX:ONC, NASDAQ: ONCY) on Feb 14th, 2011, announced promising preliminary results from a U.S. Phase 2 clinical trial  (REO 017) using intravenous administration of REOLYSIN® in combination with gemcitabine in patients with advanced pancreatic cancer. [... , ...].  REOLYSIN is a proprietary formulation of the human reovirus, an oncolytic virus. 
  
•  Peregrine Pharmaceuticals, Inc., Tustin, Calif., (NASDAQ: PPHM), is testing bavituximab, a phosphatidylserine (PS)-targeting monoclonal antibody, in stage IV pancreatic cancer (Phase II trial) [...]  PS is an immunosuppressive molecule usually located inside the membrane of healthy cells, but is externalized in tumor tissues in cells undergoing apoptosis.  When exposed outside the cell, it interferes with normal anti-tumor immune response.
• Similarly, PharmaEngine, Inc. of Taipei has PEP02, a liposome irinotecan preparation (Irinotecan HCl: Camptosar®, Campto®) in Phase II metastatic pancreatic cancer trial [... , ...] 
• Raven Biotechnologies, Inc., South San Francisco, was investigating RAV18, a monoclonal antibody in Phase II (news: ...; trials: ...]  RAV18 is a humanized antibody targeting the ADAM9 protein on cells.  Later, Raven was acquired by MacroGenics in mid-2008.  RAV18 is no longer listed on its website (pipeline).
• Threshold Pharmaceuticals Inc., Redwood City, Calif, (Nasdaq:THLD), has a compound TH-302 in phase I/II [...]
• Viralytics Limited, Sydney, (ASX: VLA, OTC: VRACY) is using Coxsackievirus A21 (CAVATAKTM), an oncolytic virus strategy.  Coxsackievirus A21 uses the ICAM-1 receptor to invade and destroy cancerous cells; pancreatic cancer cells over-express ICAM-1. [...]
• An article in February 17, 2011 issue of SciBX by Tracey Baas, describes an encapsulated tumor cell macrobead approach.  In this approach, the tumor cells are grown in agarose beads; while 99% of cells die, the remaining cells proliferate, display stem cell markers and secrete biological signals.  When implanted, these macrobeads have the potential to inhibit in situ tumors.  This approach is being tested in Phase II (read here, here)
• Amgen is testing an antibody to insulin-like growth factor 1 (IGF-1) in pancreatic cancer. [...]
• Some others in early pipeline are: glufosfamide (Baxter Oncology), mastinib (AB Science) and Abraxane (Abraxis).

Diagnostics and Biomarkers

• Reetesh Pai of Stanford last month published an article in Cancer Cytopathology showing that PAX8 immunohistochemistry in fine-needle aspiration biopsies can be used as an ancillary marker of well-differentiated neuroendocrine pancreatic carcinomas
• At Feb. 2011 ASCO Gastrointestinal Cancers Symposium, David Chang of New South Wales Pancreatic Cancer Network presented data showing correlation between calcium-binding proteins, S100A2 and S100A4 expression in tumors and poor survival post-surgery.  Patients with S100A2+/A4+ tumors had three times lower survival (34.3 vs. 11.9 months in A2-/A4-); those with S100A4+ only had intermediate survival (15.6 months).  S100A2 and S100A4 (aka MTS1, metastasin, FSP1, and p9ka) protein expression has been associated with metastasis, chemoresistance, and a mesenchymal phenotype in animal models.  The significance of S100A2 and S100A4 finding is that these markers will help oncologists consider more aggressive approaches for A2+/A4+ patients without delay. [..., ..., ...]
• 2011 ASCO Gastrointestinal Cancers Symposium also had presentations showing that a DNA repair gene variant RecQ1 A159C variant (rs13035) [RecQ1 A159C genotype] is a prognostic or predictive factor for resectable pancreatic cancer patients who are treated with adjuvant chemoradiation.[...]
• 2011 ASCO Gastrointestinal Cancers Symposium had a poster on MicroRNA profiles compared between pancreatic ductal adenocarcinoma (PDAC) or ampullary adenocarcinomas (A-AC) and normal pancreas. An earlier reported diagnostic miR profile for PDAC [by Szafranska et al. Clin Chem 2008;54:1716-24]was validated (mirR196b - miR217), and in addition, three additional significant miR signatures were found: mirR411 - miR198, mirR614 - miR122, and mirR614 - miR93. [...]
• A 2009 epidemiological study (n>1000,000) published by researchers at Dana-Farber Cancer Institute in the Journal of the National Cancer Institute found that compared to people with type O blood, the risk of pancreatic cancer was 32%, 72% and 51% in those with type A, B and AB blood, respectively [..., ...]
• 'Distillery: Therapeutics – Cancer'  section in SciBx magazine (Feb. 24, 2011) reported "Genomic studies identified mutations that could help guide treatment of pancreatic neuroendocrine tumors.  Multiple endocrine neoplasia I (MEN1; menin); death-domain associated protein (DAXX); α-thalassemia/mental retardation syndrome X-linked (ATRX); mammalian target of rapamycin (mTOR; FRAP; RAFT1) [...]
• In vitro and mouse studies suggest that inhibiting MicroRNA-301a (miR-301a) could help treat pancreatic cancer. SciBX Jan. 6 2011 issue [...]
• Experimental diagnostic serum biomarkers, CA19‐9, macrophage inhibitory cytokine 1 (MIC‐1), phosphoglycerate kinase 1 (PGK1) or CEACAM1, a member of the human embryonic carcinoma antigen family, do not appear to have required sensitivity or specificity.  However, microRNA signatures consisting of KRAS, MBD3L2, ACRV1 and DPM1 showed promise in a recent study.[...]
• Genetic markers overexpressed in pancreatic cancer, include K-RAS, EGFR and p16INK4A.  These are likely prognostic biomarkers.
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• Pancreatic Cancer Clinical Trials search:  eClinicalTrials.com

Primer: The disease

Pancreatic cancer can be broadly lumped into pancreatic neuroendocrine tumors (PNET) or islet cell tumors, and pancreatic ductal adenocarcinoma (PDAC).  PNETs account for just 1.4% of all cases, but unlike PDACs, they have a good prognosis.  On the other hand, PDACs that represent the bulk of pancreatic cancers (and is synonymous to pancreatic cancer in clinical practice or public eye) have a survival rate of just one to two years.  The lifetime risk of pancreatic cancer is 1 in 72 and it is the fourth deadliest form of cancer in the United States.  It kills approximately 35,000 people a year (2010 statistics).  

Exact causes are unknown; risk factors include, family history, hereditary pancreatitis, PALB2 and BRCA 2 gene mutations, smoking, obesity and diabetes.  The disease usually strikes after age 45.  It is often misdiagnosed because the symptoms, including weakness, weight loss, nausea, loss of appetite, jaundice are shared with other GI diseases.  Famous actor, Michael Landon (died 1991)who succumbed to pancreatic cancer within a year of diagnosis, told his Tonight Show host how he felt that the pain was due to ulcer, as a result he was not diagnosed until very late. [...]  In an interview with Barbara Walters, before his death, Patrick Swayze said, "You can bet that I'm going through hell, and I've only seen the beginning of it."[...]

Early diagnosis remains a challenge.  Tumors are not palpable because of the deep location of pancreas in the abdomen.  Diagnosis occurs often after persistent complaints of pain in upper abdomen and/or back, using imaging techniques (MRI, CT scan or ultrasound), followed by biopsy.  In most patients, this diagnosis comes too late, with fewer options for oncologists. (wikipedia)  In December last year, Myriad Genetics launched Panexia™, a predictive test for hereditary pancreatic and related cancers. Panexia analyzes the PALB2 and BRCA2 genes. (read here)

The extent of spread is described as Stages O to IV:  Stage O, no spread and limited to single layer of cells; Stage I, local growth of 2 cm [1A] or more [1B]; Stage II, local spread, including nearby  lymph nodes; Stage III, wider spread, now includes nearby blood vessels and nerves, but not other organs; and Stage IV, spread to distant organs.  Surgery is an option for "resectable" tumors up to Stage II or III.  About 60% of tumors occur in the head of pancreas are resectable.  The most common surgical procedure is Whipple procedure (aka pancreatico-duodenectomy), wherein the surgeon removes the head of pancreas and parts of surrounding organs (stomach, small intestine, local lymph nodes, gallbladder, and common bile duct.) The remaining organs are reconnected to allow digestion.  Distal or total pancreatectomy procedures are relatively uncommon.  Surgery is an option for only 15-20% of patients.  Chemotherapy and radiation therapy are used with or without surgery. 

Gemcitabine (Gemzar, Eli Lilly) and 5-fluorouracil (5-FU) are the most common chemotherapy drugs used in pancreatic cancer.  Gemcitabine is the current standard treatment for advanced pancreatic cancer.  With metastatic and advanced cancer, the therapy is palliative, with morphine, pain management and antidepressants.  Recent trials combining gemcitabine with bevacizumab (Avastin) or aflibercept failed in Phase III; similarly cetuximab (Erbitux) or capecitabine (Xelada) have either shown no benefit or are still ongoing (read review)  Erlotinib has been approved as a first‐line treatment in combination with gemcitabine for metastatic pancreatic cancer.

Recent trials have shown superior performance of FOLFIRINOX (5-FU, irinotecan, and oxaliplatin) over gemcitabine in patients with metastatic pancreatic cancer; FOLFIRINOX may become a preferred choice over Gemcitabine or 5-FU. [...]

Getting Support/ nonprofits

Pancreatic Cancer Action Network

American Cancer Society

Cancer Care, Pancreatica, Hirshberg Foundation for Pancreatic Cancer Research

Touched by pancreatic cancer

Randy Pausch, Carnegie Mellon University

> Last Lecture

Readings 
disease and management 

• National Cancer Institute - Pancreatic Cancer [wwwLink] ; Pancreatic cancer. Treatments and drugs. Mayo Clinic Health Information [wwwLink] ; Pancreatic Cancer Treatments by Stage. WebMD 2009. [wwwLink]
• Treatment of Early-Stage Pancreatic Cancer. Emily H. Castellanos, et al. cancernetwork.com, Febl. 17, 2011  ONCOLOGY. Vol. 25 No. 2 [wwwLink]
• Patient Voices: Pancreatic Cancer at New York Times Sept. 09, 2008 [wwwLink] ; Patrick Swayze's interview with Barbara Walters, ABC News, Jan. 5, 2009 [wwwLink][...]
• What makes pancreatic cancer so deadly? Melinda Wenner.  ScientificAmerican.com, August 25, 2008 [wwwLink]

Drugs and strategies

• Everolimus for Advanced Pancreatic Neuroendocrine Tumors.  Yao et al. N Engl J Med. Feb 10, 2011;364:514-523 [Abstract] ; Sunitinib Malate for the Treatment of Pancreatic Neuroendocrine Tumors. Eric Raymond, et al. N Engl J Med. 2011; 364:501-513 [Abstract] ; (EDITORIAL) Promising Advances in the Treatment of Malignant Pancreatic Endocrine Tumors. Robert T. Jensen and Gianfranco Delle Fave, N Engl J Med. Feb. 10, 2011;364:564-565 [Abstract]
• Everolimus and Sunitinib Improve Survival in Advanced Pancreatic NET. Roxanne Nelson February 10, 2011 Medscape Medical News > Oncology [wwwLink], New cancer drugs increase survival in rare form of pancreatic cancer suffered by Steve Jobs.  By Thomas H. Maugh II, Los Angeles Times, February 10, 2011, [wwwLink]
• Randomized phase III trial comparing FOLFIRINOX (F: 5FU/leucovorin [LV], irinotecan [I], and oxaliplatin [O]) versus gemcitabine (G) as first-line treatment for metastatic pancreatic adenocarcinoma (MPA): preplanned interim analysis of the PRODIGE 4/ACCORD 11 trial. 
• Conroy T, et al.  J Clin Oncol. 2010;7(suppl):abstract 4010.
• Fighting tumors with tumors by Tracey Baas, SciBX, Feb. 17 2011, 4(7) [wwwLink, DOI]
• A molecular prognostic nomogram for resectable pancreatic cancer. David Change et al. J Clin Oncol 29: 2011 (suppl 4; abstr 154)  [wwwLink]
• Online Physician Education Program Outlines Treatment Strategies For Pancreatic Cancer. ASCO 2011 [wwwLink] 
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• Development of targeted therapies for pancreatic cancer. Philip A Philip. The Lancet Oncology, March 2011, 12(3);206 - 207 [DOI | Pubget]