Pancreatic cancer is expected to become the second leading cause of cancer-related deaths in the US in the next decade. Major risk factors for pancreatic cancer are smoking and overweight. The 5-year overall survival rate only increased from 5% to 6% in the past three decades. These abysmal survival rates demonstrate that there was no real progress in pancreatic cancer treatment!
We have to target simultaneously several critical pathways which are essential for the survival of pancreatic cancer cells! Most of these targets are protein-protein interactions. The Collaborative Modifiers™ could deliver efficient therapeutics for these known pancreatic cancer targets.
No single targeted therapy has been convincingly successful, probably due to the various mutations seen in pancreatic cancer.
The most common genetic mutations in pancreatic cancer are KRAS (90%), CDK2NA (90%), TP53 (75%–90%) and DPC4/SMAD4 (50%).
Development status: Phase 2, by AstraZeneca
Indication: Advanced or Metastatic Pancreatic Cancer, Who Have Failed First Line Gemcitabine Therapy
MOA: potent, selective, and ATP-uncompetitive inhibitor of MAPK/ERK kinase 1/2
Chronic dosing with 25 mg/kg AZD6244 bd resulted in suppression of growth of Colo-205, Calu-6, and SW-620 xenografts, whereas an acute dose resulted in significant inhibition of ERK1/2 phosphorylation. The potential of AZD6244 in combination with cytotoxic drugs was evaluated in mice bearing SW-620 xenografts. Treatment with tolerated doses of AZD6244 and either irinotecan or docetaxel resulted in significantly enhanced antitumor efficacy relative to that of either agent alone. These results indicate that AZD6244 has potential to inhibit proliferation and induce apoptosis and differentiation, but the response varies between different xenografts. phase II study patients received either 100 mg oral selumetinib twice daily or 1,250 mg/m(2) oral capecitabine twice daily for 2 weeks followed by a 1-week break, given in 3-weekly cycles. The primary endpoint was overall survival. In all 70 patients were randomized.
Development status: Phase 3, by Nucana
Indication: advanced or metastatic pancreatic cancer
MOA: ProTide transformation and enhancement of gemcitabine
Sixty-eight patients had been enrolled in the Phase I/II study, of which five patients had achieved RECIST Partial Response (tumour shrinkage of ≥30%) and an additional 33 had achieved Stable Disease. The Disease Control Rate reached an impressive 78% in the evaluable patient population. Importantly, Acelarin hasbeen well tolerated by the patients.
Development status: Phase 3,
Indication: cancer that has spread
MOA: PARP inhibitor
Phase II trial, 23 previously-treated gBRCAm mPCpatients received the PARP inhibitor olaparib (Lynparza) as monotherapy. The tumor response rate was 22%, progression-free survival (PFS) was 4.6 months and overall survival (OS) was 9.8 months. Side effects include gastrointestinal effects such as nausea, vomiting, and loss of appetite; fatigue; muscle and joint pain; and low blood counts such as anemia, with occasional leukemia.