Senior Research Professor at Indiana University School of Medicine - South Bend
Novel therapeutic strategies for pancreatic cancer, gastric cancer and cholangiocarcinoma patients:
Pancreatic cancer is one of the most aggressive cancers with extremely poor prognosis. Gemcitabine remained the standard treatment for pancreatic cancer for ~16 years despite its limited clinical effectiveness with a median survival of ~6 months. Our research demonstrated that nab-paclitaxel, a next-generation taxane, is a superior chemotherapeutic agent compared with gemcitabine or docetaxel (1). Nab-paclitaxel had an anti-mitotic and anti-stromal activity and it decreased tumor growth and increased animal survival. These findings played a significant role in the FDA approval of the nab-paclitaxel plus gemcitabine combination for pancreatic cancer. We demonstrated that the antitumor response of nab-paclitaxel plus gemcitabine standard chemotherapy of pancreatic cancer can be enhanced by targeting angiogenesis (2,3), IGFR signaling (4), KRAS signaling (5,6) and MMP9 signaling (7). We are currently evaluating enhancement in nab-paclitaxel-based chemotherapy response by targeted inhibition of other potential pathways of pancreatic cancer progression including c-MET, Axl and TGF-b. These studies will provide a better understanding of molecular mechanisms of tumor progression, novel therapeutic strategies and open realistic avenues to double the survival of pancreatic cancer patients.
Gastric cancer is the second most common cause of cancer-related death in the world. Gastric cancer patients are often treated with platinum and fluoropyrimidine-based regimen that usually has a median survival of 8 to 10 months. We have developed and optimized several highly effective, reproducible and efficient preclinical models for evaluating novel and effective therapeutic strategies to improve the outcome of gastric cancer patients. We demonstrated that nab-paclitaxel is the most effective chemotherapy agent for gastric cancer compared with contemporary commonly used chemotherapy agents (5-FU, epirubicin, oxaliplatin, docetaxel, irinotecan) (8). Also, we established that the combination of nab-paclitaxel with mechanistically different antiangiogenic agents, has significantly enhanced antitumor response (9). These studies provided the basis for conducting a clinical trial of best chemotherapy plus antiangiogenic agent combination that would probably improve the prognosis of gastric cancer patients to a significant extent.
Cholangiocarcinoma (CCA) is the second most common primary liver cancer after hepatocellular carcinoma and its incidence is increasing in Western countries. Combination of gemcitabine and cisplatin remains the standard treatment in unresectable or recurrence cases with a median survival of ~14-months. Based on our experience in pancreatic and gastric cancer, we have established preclinical CCA models for evaluating experimental therapeutics. We are currently evaluating antitumor effects of telotristat ethyl (TE) alone and in combination with standard chemotherapy in the CCA preclinical models. These studies will give us direct evidence for optimal and more effective clinical therapeutic strategies for cholangiocarcinoma patients.
1. Awasthi N, et al. (2013). Carcinogenesis 34:2361-69
2. Awasthi N, et al. (2014). Mol Cancer Ther 13:1032-43
3. Awasthi N, et al. (2015). Cancer Lett 358:59-66.
4. Awasthi N, et al. (2016). Oncotarget 7(30):46988-47001.
5. Awasthi N, et al. (2017). Oncotarget 9(4):5274-5286
6. Awasthi N, et al. (2019). Cancer Lett 459:41-49
7. Awasthi N, et al. (2019). J Cell Mol Med 23:3878-3887
8. Zhang C, Awasthi N, et al. (2013). PLoS ONE 8(2):e58037.
9. Awasthi N, et al. (2018) Mol Cancer Ther (In Press).