Introduction: Epidemiological evidence highlights the influence of vitamin A (retinol) and its active metabolite, all-trans retinoic acid (ATRA) on the incidence of breast and prostate cancers in humans. ATRA is required for the appropriate cellular differentiation of normal human breast epithelial cells. In a 12-year prospective study of 208 postmenopausal women operated on for breast cancer, it was recently reported that low plasma retinol strongly predicts poorer prognosis in patients. Work by our group has identified novel and potent inhibitors of CYP26 enzymes responsible for intracellular catabolism of ATRA into inactive metabolites. These CYP26 inhibitors are also called retinoic acid metabolism blocking agents (RAMBAs). Our novel agents, in addition to inhibiting ATRA metabolism, also possess multiple desirable anti-breast cancer properties, and hence are called atypical RAMBAs. Our lead compound, 4-(1)-(1H-imidazol-1-yl)-(E)-retinoic acid (VN/14-1) exhibits exceptional anti-tumor efficacy in several endocrine-sensitive and insensitive (i.e., tumors that are resistant to mainstay breast cancer therapies such as tamoxifen and aromatase inhibitors) breast cancer xenograft models. VN/14-1 also inhibits the growth of tumors in the N-methyl-N-nitrosourea (MNU)-induced estrogen receptor (ER) positive rat mammary model and antagonizes the stimulatory effect of estradiol on the uterus. In contrast to its effects on several breast cancer cell lines, the compound exhibits virtually no growth inhibition (at concentrations up to 100 ?M) of normal human breast epithelial and fibroblast cells. The University of Maryland, Baltimore (UMB, the PI's former institution) has entered into a clinical research agreement with Cancer Research UK (CRUK) to conduct the first in human study of VN/14-1. Chesapeake BioDiscovery Management LLC (CBDM), Baltimore has recently licensed the entire RAMBAs technology from UMB. It may also be relevant to state here that in another project, a CYP17 inhibitor /androgen receptor modulator, VN/124-1 (now called TOK-001) invented by the PI of this application recently received FDA investigational new drug (IND) approval for phase I/II clinical trials in prostate cancer patients. Although VN/14-1 has outstanding oral bioavailability (%F >100%) in rat and anti-tumor efficacy, it has a short half-life of 0.34 and 1.41 hr, in mouse and rat, respectively. Therefore, in this application, one of our goals is to design and synthesize new analogs with improved in vivo stability and with anti-breast cancer activities as VN/14-1 or better. We envision that such agent would possess enhanced efficacy and a larger therapeutic index than VN/14- 1. In addition, we propose to investigate the therapeutic potential and mechanisms of action the new lead compounds and either of the two enantiomers of VN/14-1, i.e., (+) and (-)-VN/14-1. This strategy is based on several literature precedents which show that the enantiomers in a chiral compound/drug generally show significant differences in their pharmacokinetics (PK), pharmacodynamics (PD) and adverse reactions. Therefore, it is important to know the individual isomer effects on the potency, drug-likeness and efficacy so that we can avoid the adverse effects of the other isomer, if any. Hypothesis: Using our lead racemic VN/14-1, we have established proof-of-principle of the efficacy of this class of RAMBAs in many in vitro and in vivo models of human and murine breast cancers. The major hypothesis to be tested as described in this revised application is that development (identification) of 2nd generation atypical RAMBAs, new analogs of VN/14-1 with enhanced metabolic stability, drug-likeness and efficacy can potentially be developed as new therapy for breast cancer (inhibition of tumor growth and metastasis). Objectives: To test this hypothesis, and to maximize the probability of achieving our ultimate goal while using resources most efficiently, we will carry out four specific aims: 1) To synthesize enantiomers of lead VN/14-1 and to modify VN/14-1 to produce more potent/metabolically stable/efficacious drug-like analogs;2) To extensively characterize and evaluate new analogs as RAMBAs and as anti-proliferative agents of human breast cancer cells;3) To determine the mechanism of action of the lead compound and best analogs in human breast cancer cell line;and 4) To test the lead compound and best analogs for their ability to inhibit breast cancer growth, inhibit breast cancer metastasis in vivo and identify markers of efficacy. Significance: Our ultimate goal is to discover and develop new orally active drugs for breast cancer capable of inhibiting the growth of tumor cells and metastasis. Importantly, the atypical RAMBAs inhibit both endocrine- sensitive and endocrine resistant (refractory to endocrine therapies) breast cancers, and also antagonize uterine hyperplasia, characteristics that are distinct from those of selective estrogen receptor modulators (SERMs), such as tamoxifen and aromatase inhibitors (AIs). The proposed studies if successfully conducted will identify at least one or two highly optimized, orally efficacious atypical RAMBAs suitable for advanced preclinical development for breast cancer therapy. The studies would also lead to the identification of biomarkers that would be useful in clinical trials.
More effective treatments are urgently needed to improve the outcome of millions of breast cancer patients. The goal of this grant proposal is to develop a metabolically more stable and efficacious analog of VN/14-1 (i.e., 2nd generation atypical RAMBA) for breast cancer therapy. The novelty of the proposal is that it might advance the development of new agents that might be useful for the treatment and prevention of a variety of breast cancers, including endocrine-sensitive, endocrine-resistant and metastatic breast cancer, phenotypes that are responsible for mortality attributed to this disease. In addition, we envision that because of the multi-target nature of VN/14-1 analog lead agent(s), the likelihood of drug resistance in breast cancer patients will be reduced. We strongly believe that the proposed studies will fulfill the requirements for advanced preclinical studies with 1-2 candidates in view of Phase 1 study in breast cancer patients.
|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|
|Njar, Vincent C O; Brodie, Angela M H (2015) Discovery and development of Galeterone (TOK-001 or VN/124-1) for the treatment of all stages of prostate cancer. J Med Chem 58:2077-87|
|Kwegyir-Afful, Andrew K; Ramalingam, Senthilmurugan; Purushottamachar, Puranik et al. (2015) Galeterone and VNPT55 induce proteasomal degradation of AR/AR-V7, induce significant apoptosis via cytochrome c release and suppress growth of castration resistant prostate cancer xenografts in vivo. Oncotarget 6:27440-60|
|Mbatia, Hannah W; Ramalingam, Senthilmurugan; Ramamurthy, Vidya P et al. (2015) Novel C-4 heteroaryl 13-cis-retinamide Mnk/AR degrading agents inhibit cell proliferation and migration and induce apoptosis in human breast and prostate cancer cells and suppress growth of MDA-MB-231 human breast and CWR22Rv1 human prostate tumor xenogra J Med Chem 58:1900-14|
|Ramamurthy, Vidya P; Ramalingam, Senthilmurugan; Gediya, Lalji et al. (2015) Simultaneous targeting of androgen receptor (AR) and MAPK-interacting kinases (MNKs) by novel retinamides inhibits growth of human prostate cancer cell lines. Oncotarget 6:3195-210|
|Godbole, Abhijit M; Ramalingam, Senthilmurugan; Ramamurthy, Vidya P et al. (2014) VN/14-1 induces ER stress and autophagy in HP-LTLC human breast cancer cells and has excellent oral pharmacokinetic profile in female Sprague Dawley rats. Eur J Pharmacol 734:98-104|
|Ramalingam, Senthilmurugan; Gediya, Lalji; Kwegyir-Afful, Andrew K et al. (2014) First MNKs degrading agents block phosphorylation of eIF4E, induce apoptosis, inhibit cell growth, migration and invasion in triple negative and Her2-overexpressing breast cancer cell lines. Oncotarget 5:530-43|
|Tran, Kim; Risingsong, Renee; Royce, Darlene B et al. (2013) The combination of the histone deacetylase inhibitor vorinostat and synthetic triterpenoids reduces tumorigenesis in mouse models of cancer. Carcinogenesis 34:199-210|
|Purushottamachar, Puranik; Godbole, Abhijit M; Gediya, Lalji K et al. (2013) Systematic structure modifications of multitarget prostate cancer drug candidate galeterone to produce novel androgen receptor down-regulating agents as an approach to treatment of advanced prostate cancer. J Med Chem 56:4880-98|
|Goss, Paul E; Qi, Shangle; Hu, Haiqing et al. (2012) Anti-tumor effects of a novel retinoic acid metabolism blocking agent VN/14-1 in the N-methyl-N-nitrosourea-induced rat mammary carcinoma model and its effects on the uterus. Breast Cancer Res Treat 133:137-44|
Showing the most recent 10 out of 14 publications