Recent studies in our laboratory and others demonstrate that the CDK5 gene or its coactivators is amplified in a majority of human pancreatic cancers, expressed in all pancreatic cancer cell lines tested and that CDK5 activity increases as a consequence of the action of mutant k-Ras, which in turn enhaces pancreatic cancer cell growth, invasion and metastasis. We present evidence that the inhibition of CDK5 with a 3, 5- disubstituted pyrazole significantly reduces tumor size, metastasis, and vascularization of pancreatic tumors growing as xenografts in nude mice. We propose to study the effects of CDK5 inhibition on pancreatic adenocarcinoma progression in two distinct mouse models that recapitulate the human disease as it progresses from pancreatitis to PanIN lesions and from PanIN formation through metastasis. This study will focus on inhibiting CDK5 alone during early disease development and evaluate the therapeutic capacity of inhibiting CDK5 in later disease progression, using the inhibitor and Gemcitabine-Abraxane. A second benefit of inhibiting CDK5 is that it reduces pain, given its role in nociceptive signaling. Consequently, we will also undertake preclinical studies to determine if CDK5 inhibition blocks pain associated with pancreatitis and tumor growth. We will also undertake a Phase I human clinical trials that evaluate the clinical utility of inhibiting CDK5 in advanced pancreatic cancer patients that have failed other therapy options. In the longer term these studies may enable Phase II clinical trials for treateing pancreatitis and pancreatic cancer. We will also undertake parallel drug design studies to develop next-generation molecules that improve targeting of CDK5 in pancreatic cancer patients.
The research proposed in this project will explore the capacity of a new class of molecules that inhibit the activity of CDK5 in pancreatic cancer. These inhibitors have the potential to inhibit disease progression in premalignant and malignant lesions, and tumor associated pain. If successful these inhibitors will benefit every type of pancreatic cancer patient including those that have failed other therapies.
|Wang, Gang; Biswas, Anup K; Ma, Wanchao et al. (2018) Metastatic cancers promote cachexia through ZIP14 upregulation in skeletal muscle. Nat Med 24:770-781|
|Murthy, Divya; Attri, Kuldeep S; Singh, Pankaj K (2018) Phosphoinositide 3-Kinase Signaling Pathway in Pancreatic Ductal Adenocarcinoma Progression, Pathogenesis, and Therapeutics. Front Physiol 9:335|
|Barkeer, Srikanth; Chugh, Seema; Karmakar, Saswati et al. (2018) Novel role of O-glycosyltransferases GALNT3 and B3GNT3 in the self-renewal of pancreatic cancer stem cells. BMC Cancer 18:1157|
|Rana, Sandeep; Sonawane, Yogesh A; Taylor, Margaret A et al. (2018) Synthesis of aminopyrazole analogs and their evaluation as CDK inhibitors for cancer therapy. Bioorg Med Chem Lett 28:3736-3740|
|Roy, Sohini; Bag, Arup K; Dutta, Samikshan et al. (2018) Macrophage-Derived Neuropilin-2 Exhibits Novel Tumor-Promoting Functions. Cancer Res 78:5600-5617|
|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|
|Wiest, Edwin J; Smith, Heather Jensen; Hollingsworth, Michael A (2018) Met receptor inhibitor SU11274 localizes in the endoplasmic reticulum. Biochem Biophys Res Commun 501:858-862|
|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|
Showing the most recent 10 out of 191 publications