Pancreatic cancer (PC) is a highly metastatic and therapy-resistant malignancy with patients presenting with local and distant metastases at the time of diagnosis. The metastatic lesions while still undetectable contribute to the lethality of te disease and hence should be treated effectively. Antibodies directed against tumor antigens are ideal vehicles for delivering cytotoxic agents including therapeutic radionuclides to the known and occult metastatic cancer cells and can be a promising therapeutic option for treating PC. However, pancreatic tumors present a complex and highly obstructive microenvironment that is characterized by insufficient and heterogeneous tumor blood flow and extensive desmoplasia. Cell surface mucin, MUC4, is promising target for PC therapy due to its specific overexpression in tumor that correlates positively with disease progression and negatively with patient survival. Monoclonal antibody MAb 8G7, due to its reactivity to a repetitive epitope on MUC4, can potentially serve as a highly efficient targeting agent for PC. The central hypothesis of this proposal is: MUC4 is a novel molecular target for targeted radionuclide therapy (TRT) of lethal pancreatic cancer and selective modulation of tumor microenvironment can improve the delivery and enhance the therapeutic efficacy of MUC4-targeted radiopharmaceuticals. The overall objective of the proposed studies is to determine the utility of targeting pancreatic cancer with novel radiolabeled anti-MUC4 antibodies in combination with rationally-selected specific modulators of tumor microenvironment (TME). Tumor vasculature is characterized by structural and functional anomalies as compared to normal vasculature and these differences result in differential responses when the normal and tumor vasculature are exposed to various vasoactive agents. Modulation of tumor stromal compartment can be achieved by selectively targeting the signaling pathways that regulate various components of tumor stroma.
Three specific aims are proposed: 1) Evaluation of MUC4 as a target for TRT of PC; 2) Selective Modulation of tumor microenvironment for improved delivery of radiopharmaceuticals; and 3) Determine the therapeutic efficacy of MUC4 and TME targeted combination therapy.
Aim 1 will provide information about the efficiency of anti-MUC4 MAb for targeting PC in vivo and characterize the MAb in terms of biodistribution and pharmacokinetics. Further, the studies will allow us to determine which therapeutic radionuclide is compatible with anti-MUC4 MAb.
Aim 2 will evaluate a combination of tumor-selective agents for their ability to improve TME in xenograft and autochthonous tumors for enhanced delivery of radiopharmaceuticals.
Aim 3 will allow us to determine if the improved delivery, distribution and retention of radiolabeled antibodies translates to improved therapeutic efficacy. The proposed studies represent the first comprehensive effort to overcome physiological barriers for macromolecular radiopharmaceuticals and utilize clinically relevant transgenic mouse models of PC. The preclinical results obtained from the proposed study will form the basis of clinical trial in PC patients.
The proposed studies are aimed at developing an effective targeted radionuclide therapy (TRT), based on novel MUC4 antibodies and specific modulation of tumor microenvironment. The studies will exploit the unique specificity of anti-MUC4 towards tumor cells and tumor-selective nature of modulators of tumor microenvironment. The studies will further exploit power of transgenic animal models that develop autochthonous tumors and recapitulate the complexities of human tumors and are hence accurate predictors of clinical responses.
| Chugh, Seema; Barkeer, Srikanth; Rachagani, Satyanarayana et al. (2018) Disruption of C1galt1 Gene Promotes Development and Metastasis of Pancreatic Adenocarcinomas in Mice. Gastroenterology 155:1608-1624 |
| Jahan, Rahat; Macha, Muzafar A; Rachagani, Satyanarayana et al. (2018) Axed MUC4 (MUC4/X) aggravates pancreatic malignant phenotype by activating integrin-?1/FAK/ERK pathway. Biochim Biophys Acta Mol Basis Dis 1864:2538-2549 |
| Cannon, Andrew; Thompson, Christopher; Hall, Bradley R et al. (2018) Desmoplasia in pancreatic ductal adenocarcinoma: insight into pathological function and therapeutic potential. Genes Cancer 9:78-86 |
| Aithal, Abhijit; Junker, Wade M; Kshirsagar, Prakash et al. (2018) Development and characterization of carboxy-terminus specific monoclonal antibodies for understanding MUC16 cleavage in human ovarian cancer. PLoS One 13:e0193907 |
| Hall, Bradley R; Cannon, Andrew; Atri, Pranita et al. (2018) Advanced pancreatic cancer: a meta-analysis of clinical trials over thirty years. Oncotarget 9:19396-19405 |
| Banerjee, Kasturi; Kumar, Sushil; Ross, Kathleen A et al. (2018) Emerging trends in the immunotherapy of pancreatic cancer. Cancer Lett 417:35-46 |
| Gautam, Shailendra K; Kumar, Sushil; Cannon, Andrew et al. (2017) MUC4 mucin- a therapeutic target for pancreatic ductal adenocarcinoma. Expert Opin Ther Targets 21:657-669 |
| Krishn, Shiv Ram; Kaur, Sukhwinder; Sheinin, Yuri M et al. (2017) Mucins and associated O-glycans based immunoprofile for stratification of colorectal polyps: clinical implication for improved colon surveillance. Oncotarget 8:7025-7038 |
| Macha, Muzafar A; Rachagani, Satyanarayana; Qazi, Asif Khurshid et al. (2017) Afatinib radiosensitizes head and neck squamous cell carcinoma cells by targeting cancer stem cells. Oncotarget 8:20961-20973 |
| Kumar, Sushil; Cruz, Eric; Joshi, Suhasini et al. (2017) Genetic variants of mucins: unexplored conundrum. Carcinogenesis 38:671-679 |
Showing the most recent 10 out of 15 publications
