Pilot Project: ImPact 2.0

MSM Co-Lead Brian Rivers, PhD
UAB Co-Lead: Reagan Durant, MD, MPH

Cancer Clinical Trials (CCT) are the cornerstone of clinical oncology research and provide the foundation for development and implementation of effective cancer therapies. Yet, the most recently published analysis of national enrollment data from breast, lung, prostate, and colon cancer trials, sponsored by the National Cancer Institute (NCI) between 2000 and 2002, show that only 1.3% of eligible African Americans (AAs) were enrolled in CCTs. Although many interventions have focused on approaches to increase the willingness of AAs to participate in CCTs perhaps efforts should be focused on increasing the opportunities among AAs to participate in CCTs. One such promising intervention, the IMPaCT program of the O' Neal Cancer Center, increased AA participation in clinical trials from 11% to 21% over a four-year span. We propose to augment and adapt the IMPaCT patient navigation model, IMPaCT 2.0, for implementation at Morehouse Healthcare (MH) and Grady Hospital (Grady), one of the largest safety-net hospitals in the nation to increase AA participation in clinical trials (currently less than 10%). The proposed research is novel because of the 1) enhancement of the patient navigation (PN) model for clinical trials with a dual focus on AA recruitment and retention, and 2) integration of CTNs with a mobile tablet CTTS intervention for matching of AAs with clinical trials at a safety-net hospital and a less research-intense environment.

CD24-Dependent Inactivation of Mutant p53 in Metastatic Castration-Resistant Prostate Cancer

MSM Co-Lead James W. Lillard, Jr., PhD, MBA
UAB Co-Lead: Lizhong Wang, PhD

African American (AA) men have the highest rate of prostate cancer (PC) among any racial or ethnic group [1]. They also have a higher rate of death due to development of metastatic and castration-resistant PCs (CRPCs). In a U54 CA118948 Pre-Pilot project, we found that, in AA PC cases, CD24 expression in PC tumors was associated with an aggressive tumor stage, especially with distant metastasis. We also identified distributions of the CD24 genetic variant among AAs, European Americans (EAs), and Asians. In particular, highly expressed alleles of CD24 were more frequent in AAs than in EAs and Asians, which should result in higher levels of CD24 expression in AA PC cases (see our preliminary data). Furthermore, our bioinformatic analysis of public datasets found that a higher level of CD24 mRNA expression correlated with later stage and metastatic PC. We therefore hypothesize that CD24 promotes mutant p53 inactivation, which contributes to tumor metastasis in AA CRPC patients. Our results will provide a better understanding of CRPC metastasis, especially in AA PC patients. Since silencing of CD24 functionally restores (mutant) p53 CD24 may be a therapeutic target. Validating our hypothesis will create a new target for the treatment of metastatic CRPCs, benefitting those at a higher risk for developing this type of cancer, especially AA men.

Molecular Regulation of KAISO in Prostate Cancer

TU Co-Lead: Clayton C. Yates, PhD
UAB Co-Lead: William E. Grizzle, MD, PhD

Although prostatic adenocarcinoma is the most commonly diagnosed cancer in U.S. males, the death rate from this cancer is lower than would be expected. African Americans (AAs) who have prostate cancer (PCa) typically have more aggressive disease and make up a disproportionate number of the deaths from this disease; however, many patients with PCa do not die of PCa even if untreated (i.e., indolent PCa). We have recently studied expression of the molecule, Kaiso, in PCa and found that Kaiso is increased in aggressive PCas, especially in PCas of AAs. Also, we have found that Kaiso is involved in facilitating the epigenetic suppression of genes (e.g., E-cadherin) and, via this silencing of specific genes, causes the epithelial-to-mesenchymal transition (EMT) in PCas. Therefore, the objectives of our proposal are to demonstrate the molecular mechanisms regulating the nuclear expression of Kaiso and to show that Kaiso can be targeted therapeutically to reduce EMT and associated metastases of PCa. Based on the above, and preliminary findings pointing towards a role for Kaiso in the phenotypic plasticity that underlies tumor dissemination, we hypothesize that subcellular localization of Kaiso can be targeted to limit dissemination and prevent metastatic tumor growth.

Role of leptin-Notch axis in pancreatic cancer

MSM Lead: Ruben Gonzalez-Perez
UAB Lead: Chris Klug, PhD

This project will investigate: (1) whether obesity and leptin-Notch signaling are critical for pancreatic cancer (PC) development, PC stem cells (PCSC) and drug resistance; (2) whether PC from patients of different ethnicities respond differently to leptin signaling; and (3) whether the potent, non-toxic and novel antagonist of leptin signaling we developed, IONP-LPrA2, could be an effective adjuvant for chemotherapeutics used in PC treatment. Preliminary data show that leptin stimulates PC proliferation, PCSC self-renewal and impairs PC chemotherapeutic efficacy. These investigations will help to understand whether obesity and leptin-Notch signaling could cause PC health disparity, and will help the development of novel targeted therapies and improve PC chemotherapeutic efficacies, and advance our limited understanding of the roles of obesity, and leptin signaling in PC progression and chemoresistance.

Altered Metabolic Switch and BRCA1-Associated Cancers

MSM Lead: Veena Rao, PhD
UAB Lead: Yuchang Fu, PhD

MSM Lead:Veena Rao, PhD
UAB Lead:Yuchang Fu, PhD

This project will explore the hypothesis that BRCA1 functions as a tumor suppressor through its sequestration of UBE21, a pivotal regulator of glucose transporter, resulting in regulated glucose uptake. Our recent results show that BRCA1 proteins bind to UBC9 and that the lack of binding by disease-associated mutant BRCA1 proteins resulted in deregulated Ubc9 levels and loss of growth suppression by BRCA1 proteins in TNBC. Based on these preliminary results we hypothesize that BRCA1 (by binding to Ubc9) regulates GLUT-4 facilitated glucose uptake and glycolysis resulting in tumor suppression of TNBC.

Racial differences in exosome signaling promote tumor aggressiveness in African American breast cancer patients

TU Lead: Clayton C. Yates, PhD
UAB Co-Lead: William E. Grizzle, MD, PhD

This project will delineate the role of the transcriptional repressor Kaiso, as the regulator of epithelial-to-mesenchymal transition (EMT) and chemoresistance through the transfer of genetic and epigenetic material contained in exosomes. Others and we have found that AA patients have increased expression of markers related to EMT and that this is associated with a relapse of breast tumors from front-line therapy. We will determine Kaiso’s role in regulating a novel form of cellular communication.

Racial Differences in Molecular Characteristics of Cervical Cancer and Response to Treatment

MSM Lead: Roland Matthews, MD
UAB Co-Lead: Chandrika Piyathilake, MPH, PhD

The 5-year survival rates for cervical cancer (CC) are significantly lower for African American (AA) compared to Caucasian American (CA) women. Since the underlying differences in molecular characteristics of CCs as an explanation for disparities in mortality have received little or no attention, we propose to investigate whether such differences in CCs contribute to racial differences in survival.

Dual Targeting Nanoscale Drug Delivery Systems for Treatment of Metastatic Prostate Cancer

TU Lead: Mohamed Abdalla, PhD
UAB Lead: Keshav Singh, PhD

Prostate cancer (PCa) is currently the most commonly diagnosed cancer and the second-leading cause of cancer death in men in the United States. Therapeutic options for patients with metastatic hormone-refractory PCa are very limited. This project will focus on developing dual targeting nanoscale drug delivery systems (DT-NDDSs), which will utilize a combination of a panel of novel designed peptides with enhanced binding affinities to receptors on prostate cancer (PC) cells.

Chemopreventive and Therapeutic Activity of Withania somnifera and its Mechanism of Action in Human Breast Cancer

TU Lead: Dr. Karmal Kazal
UAB Lead: Dr. Clinton Grubbs

This pilot project will test the chemopreventive and chemotherapeutic activity of an extract of Withania somnifera in experimentally induced mammary tumors and in mice bearing xenografted tumors. In addition, its cytotoxicity to breast cancer cells in relation to their expression of estrogen receptors and its mechanism of action will be evaluated. Based on the preliminary findings, the primary hypothesis is that the root extract of WS will be effective in preventing and treating breast cancer and will enhance the anti-tumor efficacy of conventional chemotherapy drugs such as tamoxifen. Successfully completed, the findings of this project will provide important evidence of its safety for future clinical use.

BRCA1 Deficiency and Epithelial Ovarian Cancers

MSM Lead: Dr. Veena Rao
UAB Lead: Dr. Charles Landen

This pilot project will determine the mechanistic and physiological significance of the interaction between BRCA1 and Ubc9 molecules in relation to their sub-cellular localization in ovarian cancer cells. Based on their preliminary results, they hypothesize that BRCA1, by binding to Ubc9, functions as a tumor suppressor and thereby inhibits growth of ovarian tumors. Also, in collaboration with William Grizzle, MD, PhD (a collaborator from UAB), these efforts will assess the clinical significance of expression of these proteins in human ovarian tissues and determine their value in early detection, drug screening, and predicting clinical outcomes.