Pancreatic cancer (pancreatic ductal adenocarcinoma, PDAC) is one of the most lethal malignant diseases with worse prognosis and, it is the 4th most common cause of cancer-related deaths in both men and women in the United States. Because pancreatic cancer is a major public health concern, the development of new therapeutic strategies for the treatment of this devastating disease is highly challenging and significant. The PI3K-Akt-mTOR and MAPK pathways are highly deregulated in pancreatic cancer. Recent studies have also implicated the most downstream signaling component of these pathways, eIF4F (specifically, eIF4E-Mnk1/2 axis) that control gene expression at the translational level towards PDAC development and to de novo and acquired drug resistant. The significance of this finding is underscored by the tremendous therapeutic potential for targeting this downstream oncogenic nexus in human PDAC and indeed other cancers impacted by these dysfunctions. In the course of studies to develop potent androgen receptor degrading agents (ARDAs) to modulate AR signaling in prostate cancer models (1), we discovered that these novel ARDAs also effectively target oncogenic eukaryotic protein translation, via modulation of Mnk- eIF4E axis. We note that these targets have been implicated in the development, progression, metastasis and drug resistance of PDAC (2-5). In addition, by targeting Mnk-eIF4E which is downstream of KRAS oncogene, we could for the first time effectively suppress the action of KRAS, a mutated oncogene present ~90% of PDAC tumors (6). We also discovered that these ARDAs are not only effective against prostate cancer cells and tumors but they are also effective anti-pancreatic cancer agents. Our preliminary results clearly demonstrate a potential use of ARDAs (VN/124-1 or galeterone and related analogs) for effective treatment of PDAC. The objective of this proposal is to test this hypothesis by blocking both Mnk-eIF4E activity in preclinical cell culture and animal models of pancreatic cancer, and will do this by using our novel ARDAs, VN/124-1 (Galeterone or TOK-001; that is poised to enter phase 3 clinical trials in castration-resistant prostate cancer patients) and its more efficacious analogs VNPP414 and VNPP433-3, which should facilitate rapid translation if these preclinical studies show promising activity.
Three specific aims will be pursued: 1) Design and develop practical synthesis of highly promising novel ARDAs, VNPP414 and VNPP433-3. 2) Determine the anti-cancer activities, mechanisms of action of lead ARDAs alone and in combination with gemcitabine (the elective drug for PDAC therapy). 3) To assess the in vivo anti-tumor and anti-metastatic efficacies of lead ADRAs in a xenograft, orthotopic and patient-derived xenograft of PDAC. This project is expected to generate new information to lay a solid foundation for future extensive mechanistic studies as well as advanced preclinical development and assessment of the oncogenic potential of targeting Mnk-eIF4E signaling as a means to novel and improved therapeutic for pancreatic cancer through other NIH funding mechanisms and possibly partnering with big/small pharmaceutical companies. We believe that the results from the proposed study will provide strong preclinical proof-of-concept for the use of multi-target ARDAs as a novel therapeutic strategy in the treatment of pancreatic cancer in humans.

Public Health Relevance

Because pancreatic cancer (PDAC) is a deadly disease with low survival rate, there is an urgent need for the development of effective and safe therapy for this difficult-to-treat disease. We have recently discovered a new class of anti-cancer agents that exert profound anti-pancreatic cancer activity through targeting of oncogenic protein translation (Mnk-eIF4E). This exploratory high-risk-high-gain R21 project will test the lead ARDA compounds (VN/124-1 (galeterone), VNPP414 and VNPP433-3) for their therapeutic efficacy and safety in clinically relevant pancreatic cancer models. By developing novel drug-like small molecules that are efficacious against several forms of PDAC including drug-resistant PDAC, we hope to obtain new drugs to enable improved outcomes for patients with this deadly disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21CA195694-02
Application #
9041559
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Arya, Suresh
Project Start
2015-04-01
Project End
2017-03-31
Budget Start
2016-04-01
Budget End
2017-03-31
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Maryland Baltimore
Department
Pharmacology
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Ramamurthy, Vidya P; Ramalingam, Senthilmurugan; Gediya, Lalji K et al. (2018) The retinamide VNLG-152 inhibits f-AR/AR-V7 and MNK-eIF4E signaling pathways to suppress EMT and castration-resistant prostate cancer xenograft growth. FEBS J 285:1051-1063
Ramalingam, Senthilmurugan; Ramamurthy, Vidya P; Njar, Vincent C O (2017) Dissecting major signaling pathways in prostate cancer development and progression: Mechanisms and novel therapeutic targets. J Steroid Biochem Mol Biol 166:16-27
Ramamurthy, Vidya P; Ramalingam, Senthilmurugan; Kwegyir-Afful, Andrew K et al. (2017) Targeting of protein translation as a new treatment paradigm for prostate cancer. Curr Opin Oncol :
Kwegyir-Afful, Andrew K; Murigi, Francis N; Purushottamachar, Puranik et al. (2017) Galeterone and its analogs inhibit Mnk-eIF4E axis, synergize with gemcitabine, impede pancreatic cancer cell migration, invasion and proliferation and inhibit tumor growth in mice. Oncotarget 8:52381-52402
Njar, Vincent C O (2017) Androgen receptor antagonism and impact on inhibitors of androgen synthesis in prostate cancer therapy. Transl Cancer Res 6:S1128-S1131
Kwegyir-Afful, Andrew K; Bruno, Robert D; Purushottamachar, Puranik et al. (2016) Galeterone and VNPT55 disrupt Mnk-eIF4E to inhibit prostate cancer cell migration and invasion. FEBS J 283:3898-3918