Novel therapeutic strategies for pancreatic cancer, gastric cancer, and bile duct cancer:

Pancreatic cancer, gastric cancer, and bile duct cancer (cholangiocarcinoma) are highly challenging diseases to treat. These cancers are notably resistant to conventional therapies and are associated with very poor prognoses, often with a median survival time of less than a year. Our laboratory is dedicated to evaluating experimental therapeutics for these malignancies. We have developed several highly effective, reproducible, and efficient animal models, including subcutaneous, orthotopic, peritoneal dissemination, patient-derived xenografts, and immunocompetent humanized mouse models, to assess experimental therapeutics in pancreatic, gastric, and bile duct cancers. This work is reflected in 32 publications over the last decade in peer-reviewed cancer research journals.

The clinical and translational impact of our research is underscored by the approval of the Indiana Clinical and Translational Sciences Institute Research Grant, six Industry-Sponsored Research Grants, and five Cancer Research Foundation Grants in the past ten years. Our research objectives focus on developing novel and more effective therapeutic strategies while elucidating the mechanisms underlying the antitumor efficacy of these approaches.

In the field of pancreatic cancer, our investigations have demonstrated that nab-paclitaxel is a superior chemotherapeutic agent. Furthermore, the addition of antiangiogenic agents has been shown to enhance the antitumor response of nab-paclitaxel. These findings were instrumental in the FDA approval of the nab-paclitaxel and gemcitabine combination for the treatment of pancreatic cancer. Gastric cancer, the fourth leading cause of cancer-related deaths worldwide, presents a formidable challenge. In our research, nanoparticle formulations of chemotherapy drugs, such as nab-paclitaxel and liposomal irinotecan (nal-IRI), demonstrated superior antitumor efficacy compared to conventional chemotherapy agents. Combining nab-paclitaxel or nal-IRI with mechanistically different antiangiogenic agents significantly enhanced the antitumor response.

These studies provided the basis for conducting clinical trials to evaluate the combination of the best chemotherapy and antiangiogenic agents in advanced gastric cancer patients, aiming to improve patient prognosis. In summary, our research endeavors in pancreatic, gastric, and bile duct cancers aim to develop innovative and more effective therapeutic approaches. By unraveling the mechanisms underlying their antitumor efficacy and leveraging preclinical models, our laboratory strives to contribute to the advancement of personalized and targeted therapies, ultimately enhancing the clinical outcomes for patients with these challenging malignancies.

Relevant publications from the past five years:

1. Awasthi N, Schwarz MA, Kaurich Q, Zhang C, Hilberg F, Schwarz RE. 2023. Enhancing gastric cancer conventional chemotherapy effects by triple angiokinase inhibitor nintedanib in preclinical models. Front Oncol 13:1145999.
   
2. Zhang J, Darman L, Hassan S, von Holzen U, Awasthi N. 2023. Targeting KRAS for the potential treatment of pancreatic ductal adenocarcinoma: Recent advancements give hope. Oncology Reports 50:206.

3. Hassan S, Awasthi N, Ponna S, von Holzen U. 2023. Nab-paclitaxel in the treatment of gastrointestinal cancers- improvements in clinical efficacy and safety. Biomedicines 11:2000.

4. Awasthi N, Schwarz MA, Zhang C, Klinz SG, Florence M-L, Beaufils B, Thiagalingam A, Schwarz RE. 2022. Augmenting experimental gastric cancer activity of irinotecan through liposomal formulation and antiangiogenic combination therapy. Mol Cancer Ther 21:1149-1159.
   
5. Crawford K, Bontrager E, Schwarz MA, Chaturvedi A, Lee DD, Hassan MS, von Holzen U, Zhang C, Schwarz RE, Awasthi N. 2021. Targeted FGFR/VEGFR/PDGFR inhibition with dovitinib enhances the effects of nab-paclitaxel in preclinical gastric cancer models. Cancer Biol Ther 22:619-629.
   
6. Grojean M, Schwarz MA, Schwarz JR, Hassan S, von Holzen U, Zhang C, Schwarz RE, Awasthi N. 2021. Targeted dual inhibition of c-Met/VEGFR2 signaling by foretinib improves antitumor effects of nanoparticle paclitaxel in gastric cancer models. J Cell Mol Med 25:4950-4961.
   
7. Awasthi N, Kronenberger D, Stefaniak A, Hassan MS, von Holzen U, Schwarz MA, Schwarz RE. 2019. Dual inhibition of the PI3K and MAPK pathways enhances nab-paclitaxel/gemcitabine chemotherapy response in preclinical models of pancreatic cancer. Cancer Lett 459:41-49.
   
8. Awasthi N, Mikels-Vigdal AJ, Stefanutti E, Schwarz MA, Monahan S, Smith V, Schwarz RE. 2019. Therapeutic efficacy of anti-MMP9 antibody in combination with nab-paclitaxel-based chemotherapy in pre-clinical models of pancreatic cancer. J Cell Mol Med 23:3878-3887.
   
9. Zhou Z, Xia GK, Xiang Z, Liu M, Wei ZW, Yan J, Chen W, Zhu JT, Awasthi N, Sun X, Fung KM, He Y, Li M, Zhang CH. 2019. A C-X-C chemokine receptor type 2-dominated crosstalk between tumor cells and macrophages drives gastric cancer metastasis. Clin Cancer Res 25:3317-3328.