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Last Updated: 09/16/21

Understanding and Addressing Cancer Health Disparities in Louisiana

Louisiana State University Health Sciences Center

Principal Investigator(s):

Augusto Ochoa, MD
Augusto Ochoa, MD

Lucio Miele, MD, PhD
Lucio Miele, MD, PhD

Principal Investigator(s) Contact Information

Augusto Ochoa, MD
Director, Stanley S. Scott Cancer Center
Louisiana State University Health Sciences Center
1700 Tulane Avenue
New Orleans, LA 70112
(504) 210-2828

Lucio Miele, MD, PhD
Professor and Department Head, Department of Genetics
Louisiana State University Health Sciences Center
533 Bolivar Street
New Orleans, LA 70112
(504) 568-8088

Overview

Cancer health disparities disproportionately affect minority and underserved populations in the Gulf South region. Malignancies such as triple-negative breast cancer (TNBC), hepatocellular carcinoma, endometrial cancer, advanced prostate, and kidney cancer have a high incidence and mortality in Louisiana (LA). Socioeconomic determinants and access to health care may explain these inequalities. Recent data suggest that genomics, inflammation, and other biological factors, such as obesity, may explain poor response to existing treatments and thus the poor outcomes. We propose to bring together investigators in our region to establish the Gulf South Center for Research and Solutions in Cancer Health Disparities. TNBC is a genetically heterogeneous, clinically aggressive malignancy that represents 15-20% of breast cancers in women. TNBC has a higher incidence and mortality in African-American (AA) women. The higher mortality rate remains a major health disparity even when controlling for the type of treatment, with 5-year survival rates around 14% in AA compared to 37% for non-Hispanic white women. Although the reasons are likely multifactorial, we propose that the decreased survival may in part result from the lower efficacy of current neoadjuvant chemotherapies, which worsens the outcome of this disease. A large fraction of TNBC cases are poorly responsive to neoadjuvant chemotherapy and have dismal long-term prognoses.

The type of immune infiltration and the expression of immunity-related transcripts have gained major significance as prognostic indicators of breast cancer as foci for novel therapeutic approaches. However, the role of inflammation in TNBC is poorly understood and under-investigated. Tumor immunity can be affected by tumor biology, socioeconomic and environmental factors. Our preliminary data and the literature show that patients with a higher T cell infiltration have better responses to neoadjuvant chemotherapy and better overall outcomes, suggesting that an effective T cell response is essential for successful treatment. Our data also demonstrates that TNBCs have remarkable infiltration by myeloid-derived suppressor cells (MDSCs), which impair the response to chemotherapy and immunotherapy. We found that MDSCs are dependent on fatty acid oxidation and can be inhibited using existing drugs, which enhances the efficacy of chemotherapy and immunotherapy. The large population of AA patients with TNBC in LA, therefore, presents a unique opportunity to study the disease.

Project 1: Immunogenomic Diversity in Triple-Negative Breast Cancer

Project Co-Leaders:
Lucio Miele, MD, PhD

Specific Aims

Specific Aim 1: Retrospectively determine whether the molecular portraits of TNBC and/or the expression of immunological biomarkers differ between EA and AA patients and whether obesity is associated with unfavorable immunological biomarkers irrespective of race.

Specific Aim 2: Prospectively characterize and compare genomic and immunological portraits and response to neoadjuvant treatment of stage II/II TNBC tumors from EA versus AA patients, obese versus non-obese, and pre- versus post-treatment samples in cases that do not achieve pCR.

Accomplishments

The incidence of triple-negative breast cancer (TNBC) in Louisiana is among the highest in the nation, particularly among African American (AA) women. In this project, we will explore the relationships between race, ancestry, tumor molecular portraits, and immunological biomarkers in TNBC patients from Louisiana, as well as the possible role of obesity in modifying tumor immunity. We wish to determine whether the molecular portraits of TNBC and/or the expression of immunological biomarkers differ between EA and AA patients and whether obesity is associated with unfavorable immunological biomarkers irrespective of race.

The Louisiana Tumor Registry’s (LTR) identified 3,188 TNBC cases in the state of Louisiana, between the years 2010-2016. Out of these samples, 1,123 qualify for the current study based on inclusion and exclusion criteria. As of this date, 473/500 samples have been received by the Miele lab from the LTR. Of these, 367 have been processed by the Histology Lab and 250 have been RNA-sequenced.

Preliminary analyses have identified differentially expressed signatures in obese versus non-obese TNBC and Black versus White TNBC.

Publications

Wu, J., Mamidi, T., Zhang, L., and Hicks, C. 2020. Unraveling the Genomic-Epigenomic Interaction Landscape in Triple-Negative and Non-Triple Negative Breast Cancer. Cancers, 12(6), p.1559.

Wu, J., Mamidi, T., Zhang, L., and Hicks, C. 2019. Integrating Germline and Somatic Mutation Information for the Discovery of Biomarkers in Triple-Negative Breast Cancer. International journal of environmental research and public health, 16(6), p.1055.

Wu, J., Mamidi, T., Zhang, L., and Hicks, C. 2019. Deconvolution of the Genomic and Epigenomic Interaction Landscape of Triple-Negative Breast Cancer. Cancers, 11(11), p.1692.

Hossain F, Danos D, Prakash O, et al. Neighborhood Social Determinants of Triple-Negative Breast Cancer. Front Public Health. 2019;7:18. Published 2019 Feb 18. doi:10.3389/fpubh.2019.00018

Precision Medicine and Triple-Negative Breast Cancer: Current Landscape and Future Directions. Hossain F, Majumder S, David J, Miele L. Cancers (Basel). 2021 Jul 26;13(15):3739. doi: 10.3390/cancers13153739.PMID: 34359640 

Project 2: Metabolic modulation of myeloid-derived suppressor cells to increase the efficacy of neoadjuvant chemotherapy

Project Co-Leaders:
Augusto Ochoa, MD

The primary goal for Project 2 is to “identify the mechanisms that induce and support MDSC in TNBC and test novel approaches to blocking MDSC to enhance the efficacy of current treatments or novel immunotherapies”. A new impasse has been the COVID-19 epidemic. This has resulted in a dramatic decrease in patient screening and undergoing elective surgeries. Because of this change, we have since worked on three alternative projects:

  1. Expand the study to include Luminal B patients: Luminal B breast cancer also disproportionately affects African American women. Furthermore, Luminal B breast cancer appears to be closely associated with obesity, which also disproportionately impacts African Americans. We have started collecting retrospective samples from women with Luminal B breast cancer through an effort with the Louisiana Tumor Registry. At this point, we have identified close to 200 samples and are in the process of having them shipped to the Biorepository for processing and sequencing.
  2. Obesity and Myeloid-Derived Suppressor Cells (MDSC) Studies:
    1. We also expand the studies with human MDSC obtained from commercial sources of human bone marrow. Our investigators have successfully developed a culture system by which they can generate large numbers of human MDSC which can be used for functional pharmacologic testing. At present we have demonstrated that the in vitro generated MDSC function similarly to those isolated from cancer patients. We have also conducted initial in vitro testing to determine which of the novel drugs being tested by our investigators can inhibit the MDSC found in the TNBC tumor microenvironment before being proposed for a novel clinical trial.
    2. We have initiated studies to understand the impact of obesity-related conditions on inflammatory cells. In addition, we have made novel discoveries that demonstrate that the “obese microenvironment” which we recreate in vitro using cytokine and metabolic conditions found in obese patients further induces immunosuppressive functions in MDSC.
  3. Colorectal Cancer and Lynch Syndrome in Louisiana: Preliminary epidemiological data suggests that there is an increased incidence of colorectal cancer in young men from the Acadian region of Louisiana. In collaboration with Dr. Heather Hample, we initiated a study to determine if there is an increase in Lynch syndrome among this population. The preliminary data of this project should be completed over the next couple of months.

Project 3: Sulindac enhances the responses of TNBC and CRC to chemotherapy and immunotherapy

Project Co-Leaders:
Yaguang Xi, MD, PhD

Specific Aims

Aim 1: To confirm the antitumor activity of sulindac in genetically distinct preclinical models of TNBC (C0321 and 4T1) and CRC (CT26).
1a. To test the therapeutic effect of sulindac on TNBC and CRC progression, alone and with standard chemotherapies (paclitaxel for TNBC and oxaliplatin for CRC)
1b. To test the effect of sulindac in combination with PD1 and PD-L1 antibodies

Aim 2: To elucidate the mechanisms of sulindac inhibition of TNBC and CRC progression
2a. To study the effect of sulindac on MDSC and TAM development and activities.
2b. To study the effect of sulindac on PD-1 and PD-L1 expression.
2c. To study the effect of sulindac on CSC and the tumor microenvironment through Notch and Wnt signaling pathways.

Accomplishments

Triple Negative Breast Cancer (TNBC) and Colorectal Cancer (CRC) continue to demonstrate significant disparities in incidence and outcomes. Using the Louisiana Tumor Registry (LTR) TNBC data geocoded to census tract of residence at diagnosis, we reported that neighborhood social determinants contributed to racial disparities in stage at diagnosis and survival but not in the incidence of TNBC. Obesity is highly prevalent in Louisiana and it’s linked to systemic inflammation and impaired tumor immunity. A chronic inflammatory tumor microenvironment tends to be enriched in myeloid derived suppressor cells (MDSCs) and tumor associated macrophages (TAM), which inhibit tumor immunity. It is known that active tumor immunity predicts good responses to standard chemotherapy, and apparently, immunotherapy. Recent evidence indicates that resistance to immunotherapy can be mediated by cancer stem-like cells (CSC), which cross-talk with the inflammatory tumor microenvironment through Notch, Wnt and other pathways. A readily translatable pharmacological strategy that targets CSC while enhancing tumor immunity would be highly impactful.

Numerous epidemiological and clinical studies suggest that non-steroidal anti-inflammatory drugs (NSAIDs) possess antitumor potential. Experimental studies on FDA approved NSAID, sulindac provide strong evidence for anti-neoplastic properties; however, the molecular mechanisms remain largely unknown. In this project, we aim to investigate the potential utility and mechanism of action for low dose sulindac as a modulator.

Project 4: Enhanced Therapeutic Efficacy in TNBC and CRC with combined Inhibition of DNA Repair and lmmunotherapy

Project Co-Leaders:
Hamid Boulares, PhD

Specific Aims

Specific Aim 1: To confirm m the anti-tumor activity of olaparib in genetically distinct preclinical models of TNBC (C0231 and 4T1), spontaneous TNBC and CRC (MCA-38 and CT26).

Specific Aim 2: To elucidate the mechanisms of olaparib inhibition of TNBC and CRC progression
2a. To study the effect of olaparib on MDSC and TAM development and activities.
2b. To study the effect of olaparib on T cell function (in vitro and in vivo).

Accomplishments

The efforts of last year focused on both aims. The following are the accomplishments achieved:

  1. Submitted an R01 application:

    Overall hypothesis: Metronomic PARPi doses selectively reduce the suppressive activity of MDSCs and provide an advantage to tumor-killing immune cells by reducing tumor progression and allowing for an excellent synergism with checkpoint blockers. Such synergism can be enhanced by activating TLR3 signaling pathway in STING-deficient tumors.

    We will perform the proposed studies using an integrated approach including syngeneic (cells with MSIhigh and MSS) or spontaneous (APCMin/+ and Msh2Vil1-fl/fl) mouse colon cancer models, PDX colon adenocarcinoma cells-engrafted humanized CD34+ mice, adoptive transfer, CRISPR/Cas9, RNAseq, Lyz2-cre-driven TMEM173fl/fl, TLR3-/-, and our newly generated C57BL/6 PARP-1fl/fl mice under the control of several relevant Cre strains. We will also use an ex vivo cell culture model to address some aspects of our stated hypothesis.

    We will test this paradigm-shifting hypothesis by the following Specific Aims:

    Specific Aim 1: To determine the influences of myeloid-specific or colon epithelial-specific PARP-1 deletion on tumorigenesis and intratumoral myeloid and lymphoid cell recruitment in APCMin/+ and Msh2Vil1-fl/fl mouse models of colon cancer.

    Specific Aim 2: To determine whether PARPi-based metronomic therapy synergizes with immune checkpoint inhibitors against tumor progression of MSIhigh or MSS tumors using a syngeneic and a PDX-engrafted humanized CD34+ mouse models of colon cancer.

    Specific Aim 3: To examine the mechanism(s) and therapeutic opportunities of the relationship between PARPi-based metronomic therapy and TLR3 stimulation in STING-deficient conditions and its synergistic potential with immunotherapy.

  2. We determined that the modulatory effect of olaparib on MDSC suppressive activity is partially dependent on STING but independent of DNA damage and trapping of PARP-1 onto chromatin.

Administrative Core

Core Directors:
Augusto Ochoa, MD

The Gulf South Center for Research and Solutions in Cancer Health Disparities will advance basic and translational research on Cancer Health Disparities in Louisiana and will provide the data to support the Research Projects to be submitted in a future SPORE application. Three major factors make our Center unique and difficult to reproduce elsewhere: 1) the unique and large number of minority patients affected by health disparities caused by cancer, 2) the growing number of basic, population science and clinical researchers dedicated to studying cancer and health disparities in our state and 3) the unique, multi-institutional participation in this P20 grant initiative. A key tenet of the Administrative Core (AC) is to provide leadership and direction that foster interactions among the scientific and administrative leaders of the Gulf South-CARES-CHD: the Executive Committee, the External Advisory Boards, the co-leaders of the Development Research Program, and the principal investigators of the funded Pilot Research Projects. In addition, the AC is charged with furthering communications with the investigators and leadership of the collaborating organizations.

Biostatistics and Bioinformatics Core

Core Directors:
Denise Danos, PhD

Specific Aims

Specific Aim 1: To perform genomic and transcriptomic analyses, including RNASeq, exome sequencing, ChIP-Seq, methylation profiling, copy number variant identification, ancestry determination and SNP genotyping

Specific Aim 2: To provide biostatistics and bioinformatics expertise for the design of clinical, laboratory and genomic experiments and execution of the proposed CARES projects

Specific Aim 3: To provide biostatistics and bioinformatics support on data management, analysis, visualization, integration and interpretation of data generated by proposed CARES projects

Specific Aim 4: To undertake translational biostatistics and bioinformatics research for developing novel methodology tools that address any issues that could not be addressed by existing methods

Accomplishments

The Bioinformatics and Data Science Service Center has developed a bioinformatics pipeline and developed and deployed tools for analysis of sequence data from the P20 projects. We have the Ingenuity Pathway Analysis software license for analysis and visualization of omics data. Bioinformatics staff have implemented a Globus node to allow for data transfer and data sharing among the investigators.

Developmental Research Program

Program Directors:
Yaguang Xi, MD, PhD

The goal of the Developmental Research Program (DRP) is to support innovative and promising Pilot Research Projects (PRP) for studying the population or biological basis of Health Disparities in triple negative breast cancer (TNBC) and other malignancies that disproportionately affect minority patients in Louisiana. These PRP will generate the necessary preliminary data to translate well-documented observations into fully competitive Research Projects for a future SPORE application, and may include clinical interventions or population studies to study and address cancer health disparities among our citizens. Although our primary goal is to expand the scope and depth of research on TNBC, we will consider outstanding proposals on other tumors that represent major health disparities in our community, such as liver cancer, endometrial cancer, familial prostate cancer, and colorectal cancer. Furthermore, given that one of our key research efforts in this P20 involves studying and ultimately understanding genomic and immunologic features of TNBC in order to find ways of overcoming the immunosuppressive microenvironment in TNBC, we will encourage PRP projects that address similar mechanisms in other cancers. This focus, among other things, would create a formal mechanism to develop interdisciplinary research projects with investigators at our partner institutions.