Pilot Project 1: Role of Cell Density in Molecular Variances Using Engineered Breast Cancer Cells

TU Co-Leader: Iman Hassani, PhD
UAB Co-Leader: Sooryanarayana Varambally, PhD

Modified Project Summary/Abstract Section

Breast cancer presents variable outcomes, notably impacting on some patients and resulting in higher mortality rates and treatment delays. Recent studies have highlighted elevated microvessel density, increased macrophage infiltration, higher CD8+ T cell density, and denser breast tumor tissues, suggesting links to disease aggressiveness. Despite these findings, the precise mechanisms of these differences remain elusive. The study investigates this research question through advanced three-dimensional (3D) tumor modeling techniques. The research comprises two specific aims.

First, we aim to engineer breast cancer tissues with meticulously controlled variations in cell density, where the engineered tissues are composed of a scaffold (collagen) and breast cancer cells, forming a 3D structure. Scaffold-based 3D cultures enriched with multiple cell lines of triple-negative breast cancer (TNBC) subtypes will be developed. Cell lines such as HCC1806, MDA-MB-468, HCC38, and MDA-MB-231 will capture TNBC heterogeneity, with deliberate variations in cell density introduced using innovative seeding methods and microfabrication technologies.

Second, we will undertake a comprehensive analysis to decipher molecular signatures associated with varying cell densities and spatial distribution within these 3D tissues. Leveraging imaging techniques, including phase-contrast, fluorescence, and confocal microscopy, alongside RNA sequencing technology, we will employ bioinformatics to unravel regulatory networks and signaling pathways pivotal in the cellular response to various densities. Time-series RNA sequencing will capture dynamic shifts in gene expression, providing insights into temporal aspects of cell density-induced changes. By elucidating the molecular underpinnings of breast cancer outcome differences, this research holds promise for informing targeted interventions aimed at mitigating inequalities and improving outcomes for all patients. This multidisciplinary approach not only advances our understanding of breast cancer but also underscores the importance of personalized healthcare strategies in combating this disease.

Pilot Project 2: Lung cancer screening Awareness Targeted and Tailored to Increase sCrEning (LATTICE)

MSM Co-Leader: Desiree Rivers, PhD
UAB Co-Leader: Soumya Niranjan, PhD

Modified Project Summary/Abstract Section

Lung cancer is the most common cancer in the US and kills more Americans than the next top three cancer types (breast, prostate and colorectal) combined. Currently, 85% of lung cancers are diagnosed when they have already metastasized, resulting in a poor five-year survival of 17%. Fortunately, radiographic screening for lung cancer using Low Dose Computerized Tomography (LDCT) is highly effective at identifying lung tumors at an early stage and is known to improve lung cancer mortality by 20%.

Unfortunately, ~10 years after the guidelines released, LCS utilization is woefully low, at <6%. Most individuals eligible for LCS are unaware of or confused or misinformed about (i) how lung cancer screening is performed, (ii) benefits and associated risks of screening, and (iii) causes of and associated risk factors for developing lung cancer. Although previous work has highlighted the effects of communication tools in cancer screenings, what is not known is the availability of geographically tailored awareness and education implementation strategies.

Therefore, there is a need to address these issues by developing and delivering regionally tailored awareness strategies. Our overall objective in this application is the development and delivery of a geographically tailored educational strategy to improve early detection of lung cancer in the states of Alabama and Georgia.

Aim 1 will adapt and geographically tailor existing lung cancer screening education strategies. We will adapt existing lung cancer screening education materials using Resnicow’s framework, which will be used to address unique social and cultural factors influencing this group’s screening participation.

Aim 2 will pilot test educational strategy and refine based on input from Community Advisory Board (CAB). We will use Group Concept Mapping with the CAB to determine salient social determinants of lung cancer screening and “map out” salient social factors of early detection educational strategy, as conceptualized by the participants themselves. This proposed work will aid in developing and delivering a geographically tailored educational strategy to improve early detection of lung cancer in the states of Alabama and Georgia.

Pilot Project 3: Targeting Hedgehog Signaling Pathway in Breast Cancer Therapy

MSM Co-Leader: Santosh Singh, PhD
UAB Co-Leader: Melad Dababneh, MD

Modified Project Summary/Abstract Section

Due to chemo-resistant metastases, breast cancer (BrCa) chemotherapy often fails after promising results. In 2023, the American Cancer Society predicted 43,700 BrCa deaths, an increase of 0.5% from the previous year. Due to its proliferation, frequent acquisition, chemotherapy resistance, and spread, BrCa has a high mortality rate. Advanced triple-negative breast cancer (TNBC) has the worst chemotherapy outcomes of all BrCa subtypes, with a nine-month survival rate. The high resistance and recurrence rate (30%), lack of effective targeting therapy (ER-, PR-, or HER2-), and poor prognosis render TNBC a poor treatment option.

TNBC is challenging to treat due to toxicities from traditional chemotherapies like docetaxel and paclitaxel, poor bioavailability of anti-cancer drugs, and lack of tumor cell specificity. We need new molecular targets and cancer cell-targeted anti-cancer drugs. Recent studies suggested that organs, tissues, and cells rely on Hedgehog (Hh) proteins for their growth, survival, and organization. Therefore, targeting the Hh signaling pathway could offer a safe and curative option for patients with specific subtypes of BrCa.

Many cancers, including human BrCa, have been associated with dysregulation of the Hh signal pathway involving the Sonic Hh (SHH) molecule. Alleviated SHH expression reduces the inhibitory impact of Smoothened (SMO) by attaching to its membrane receptors, Patched1 (PTCH1) or PTCH2, thereby activating transcription factors, Gli1, Gli2, and Gli3, to transcribe target genes and enrich the tumor microenvironment for growth and progression.

Due to SHH oncogenic properties and potential for inhibition, targeting SHH signals directly is a promising BrCa treatment. Although natural compounds show promise in vitro, their low bioavailability limits in vivo efficacy. One of the best-studied anti-cancer natural compounds is honokiol, a dietary photochemical isolated from Magnolia officinalis bark. It has antioxidant, anti-inflammatory, and anti-microbial properties and is used in traditional medicine.

Our initial findings strongly suggest targeting the Hh signaling molecule for TNBC treatment. This study will evaluate a new BrCa treatment method using honokiol alone or with docetaxel. Targeted delivery through gold nanoparticles may improve honokiol's low bioavailability and tumor cell non-specificity. This combination therapy should reduce docetaxel dosage synergistically. This research will allow honokiol to be used in pre- or clinical chemoprevention.

Pilot Project 4: Diagnostic and Therapeutic Impact of CEMIP and HA in High-risk Endometrial Cancers

TU Co-Leader: Deepa Bedi, MD, PhD
UAB Co-Leader: Mythere Karthikeyan, PhD

Modified Project Summary/Abstract Section

In Alabama, gynecological cancers, including endometrial cancer (EC), are among the top five causes of cancer deaths. Many patients in Alabama experience lower 5-year survival rates (62%) and face the lowest survival rates across all stages and types of EC. The growing racial gap in mortality rates, with a higher annual increase for this group of patients, highlights the urgent need for targeted research on EC in this population.

Wnt-β-Catenin (CTNNB1) pathways are known to be altered in ECs, with a recent study highlighting common mutations in EC subtypes and correlating with increased morbidity. We discovered that CTNNB1 mutations in EC lead to increased expression of a protein CEMIP/KIAA1199. CEMIP has been previously associated with aggressive colon, breast, and ovarian cancers. CEMIP is both an intracellular and a secreted protein that we have discovered to be elevated in both the tumor and stroma of a subset of ECs (using UAB patient cohorts in collaboration with the Tissue Biorepository).

CEMIP is a hyaluronidase, which increases the concentration of low molecular weight hyaluronan (HA) through cleavage. HA can be detected in serum and thus represents a direct measure of CEMIP activity. The goals of the study are to assess the expression of CEMIP in tumors and serum as a potential marker of CTNNB1-altered ECs and define the relationship between CEMIP, hyaluronan, and β-Catenin alterations, and how these factors vary in less-resourced patients, assessing CEMIP as a detectable marker in patient sera.

We will also investigate how CEMIP influences the effectiveness of Wnt pathway inhibitors in EC, particularly in the context of differential CEMIP expression and its impact on the efficacy of these inhibitors in cell models with or without CTNNB1 mutations. This aim seeks to establish CEMIP's role as a marker for predicting response to Wnt inhibitor treatments. These studies will thus delineate the unique molecular profiles of CTNNB1 mutated and CEMIP altered ECs to improve understanding of disease manifestation in patients, advance personalized treatments, and develop new hypotheses for diagnostics and therapy across all individuals in the southeastern U.S.

Full Project 1: Elucidating the Role of AAA ATPase TRIP13 in Prostate Cancer

MSM Co-Lead: Rajesh Singh, PhD
UAB Co-Lead: Sooryanarayana Varambally, PhD

To understand the different forms of Prostate Cancer classify indolent from aggressive conditions and develop effective therapeutic strategies, it is essential to investigate the underlying complex molecular events. Using an integrative approach and multiple high-throughput data sets, we nominated AAA ATPase TRIP13 as a potential oncogene in prostate cancer growth and progression. The objective of this joint full project between Morehouse School of Medicine and the O’Neal Comprehensive Cancer Center at UAB is to understand the biology of TRIP13-mediated tumorigenesis and metastasis. Since TRIP13 is an enzyme that can be inhibited by small molecules, the long-term goal is to develop compounds that specifically inhibit TRIP13 activity.

Full Project 2: Chemotherapy-induced Immunomodulation in Colon Cancer

TU Co-Lead: Temesgen Samuel, PhD
UAB Co-Lead: Pran Datta, PhD

Fewer than 15% of colorectal cancer (CRC) patients benefit from current immunotherapies. The mechanisms for these refractory states are not completely understood, and an immense gap remains in our knowledge of the immune factors involved in CRCs, especially those undergoing therapy. We propose to develop combination therapy strategies that modulate the immune microenvironment in CRCs by elucidating chemotherapy-inducible immunomodulation and identifying alternative targets adaptable to personalized medicine.

Pilot Project (Ended for Cycle Sep 1 2021 – Aug 31 2024): Racial Disparities in Lung Cancer Screening among a High-Risk Population at a Community Hospital and Academic Health System in the Southeastern US

MSM Co-Lead: Desiree Rivers, PhD
UAB Co-Lead: Soumya Niranjan, PhD

This pilot project will 1) Examine patient, provider, and system-level factors associated with Lung Cancer Screening (LCS) uptake among patients who were referred to screening at The Kirklin Clinic at UAB and Grady Hospital at MSM from 2015-2020. We will conduct a retrospective review of electronic medical records of adult men and women referred for LCS to determine individual sociodemographic factors, provider factors, and referral sources; 2) determine the barriers and facilitators of LCS uptake using semi-structured interviews with patients recently referred for screening, healthcare providers who make referrals, and administrators who oversee lung cancer screening systems at TKC and Grady; and 3) integrate results from the quantitative and qualitative phases to inform the design of a culturally tailored, multi-level intervention to promote LCS for patients at TKC and Grady.