Senior Research Professor at Indiana University School of Medicine - South Bend
Novel therapeutic strategies for pancreatic and gastric cancer patients:
Pancreatic cancer is projected to become the second most common cause of cancer-related death in the United States in 2030. Gemcitabine remained the standard treatment of advanced pancreatic cancer for more than 16 years despite its limited clinical effectiveness with a median survival of ~6 months. Nab-paclitaxel, a water-soluble albumin-bound paclitaxel, has demonstrated antitumor efficacy in several solid tumors. Our research demonstrated that nab-paclitaxel is a superior chemotherapeutic agent compared with gemcitabine, or a conventional taxane docetaxel (1). Nab-paclitaxel had an anti-mitotic and anti-stromal activity and it significantly decreased tumor growth and increased animal survival. Combination of nab-paclitaxel and gemcitabine increased gemcitabine concentration in plasma and tumor. These findings played a significant role in the recent FDA approval of the nab-paclitaxel plus gemcitabine combination for pancreatic cancer treatment. We recently established that the antitumor response of nab-paclitaxel-based chemotherapy can be enhanced by targeted inhibition of angiogenesis (2,3), insulin-like growth factor signaling (4) and KRAS signaling (5). We are currently evaluating enhancement in nab-paclitaxel-based chemotherapy response by targeted inhibition of other potential pathways of pancreatic cancer progression including MAPK-PI3K, MMP9 and TGF-b. These studies will provide a better understanding of molecular mechanisms of pancreatic cancer progression and open realistic avenues to double patient survival.
Gastric cancer is a challenging disease to treat, making it the fourth most common cancer and 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. Furthermore, less than 50% of patients respond to these therapies and a relatively large proportion of patients do not benefit from these intensive treatments. We have developed and optimized several highly effective, reproducible and efficient preclinical models for investigated novel and effective therapeutic strategies to improve the outcome of gastric cancer patients. Our research 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) (6). Also, we established that the combination of nab-paclitaxel with mechanistically different antiangiogenic agents ramucirumab, cabozantinib or nintedanib, has significantly enhanced antitumor response (7). These studies provided the basis for conducting a clinical trial of best chemotherapy plus antiangiogenic agent combination regimen in advanced gastric cancer patients that would probably improve the prognosis of gastric cancer patients to a significant extent.
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. Zhang C, Awasthi N, et al. (2013). PLoS ONE 8(2):e58037.
7. Awasthi N, et al. (2018) Mol Cancer Ther (In Press).