Full Research Projects
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Project #1 (Target Identification) - MYC Signaling in Poor Prognosis Luminal B Breast Cancer in African American Women
Lead PI: Ernest Martinez, Ph.D.
Co-Lead PI: Veronica Jones, M.D.
Co-Investigator: Maria A. Ninova, Ph.D.Abstract
Luminal-B breast cancer constitutes about 10-15% of all breast cancers and is characterized by expression of hormone receptors (ER+ and/or PR+) in the context of either low or high HER2 protein levels and a high proliferative index (Ki67>14% tumor cell positivity). Typically, Luminal-B breast cancer carries a good prognosis, albeit slightly worse than the predominant Luminal-A subtype. However, about 20% of Luminal-B breast cancers are highly aggressive and resistant to current therapies. Aggressive breast cancers disproportionally impact women of African descent. However, the biological determinants of this disparity are still largely unclear. As observed in most other cancers, aggressive therapy-resistant breast cancers - including the Luminal-B subtype - are associated with overexpression/activation of the MYC oncoprotein, a gene-specific DNA-binding transcription regulator, and activation of MYC-downstream signaling pathways. MYC is also disproportionally overexpressed in breast invasive carcinoma from Black/African American patients relative to Caucasian/white women. Hence MYC is an attractive target to combat aggressive therapy-resistant breast cancers and improve survival of women of African descent. However, attempts to therapeutically target the MYC protein have so far failed. In addition, systemic MYC inactivation is expected to have unwanted side effects in normal self-renewing/regenerating tissues since MYC regulates many genes essential for normal cell growth, proliferation, and differentiation. Our recent studies indicated that the ability of overexpressed MYC to transform normal cells into malignant tumor-forming cells is dependent on specific amino acid (lysine) residues of MYC that are chemically modified (acetylated) by histone acetyltransferases. Importantly, these acetylated lysine (AcK) residues are also key for MYC regulation of a select number of genes but dispensable for regulation of most MYC-dependent genes and for proliferation of normal cells in vitro. Thus, we hypothesize that targeting of MYC AcK-dependent signaling mechanisms and pathways could be an effective strategy to selectively inhibit growth of aggressive Luminal-B breast cancer with fewer side effects on normal proliferating cells and tissues. This project will (1) characterize the factors and mechanisms underlying MYC AcK-dependent regulation of select target genes, and (2) define the role of MYC AcK-dependent signaling in Luminal-B breast cancers from women of African descent (Black and Afro-Latina women). The identification of gene-selective MYC signaling mechanisms and pathways driving aggressive Luminal-B breast cancers will advance our long-term goal to improve survival of women of African descent who are most impacted by this disease.
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Project #2 (Drug Development) - Development of Inhibitors of the PIN1 Oncoprotein in Pancreatic Cancer
Lead PI: Maurizio Pellecchia, Ph.D.
Co-Lead: Mustafa Raoof, M.D., M.S.
Co-Investigators: Gregor Blaha, Ph.D., David Horne, Ph.D.Abstract
Pancreatic cancer has one of the worst survival rates (~12%) of all cancers. Compared to non-Hispanic white patients, Black patients have ~25% increased incidence rates of pancreatic cancer and are diagnosed at an earlier age (NCI SEER program). Socioeconomics and biologic factors are thought to contribute to this health disparity. The cis-trans prolyl isomerase PIN1 controls many cancer pathways via proline-mediated phosphorylation of diverse signaling proteins and is overexpressed both in pancreatic cancer cells and cancer-associated fibroblasts. PIN1 overexpression is a major contributor to tumorigenesis, activating several oncoproteins (e.g., in the KRAS pathway) and simultaneously inactivating several tumor suppressors. Genetic and pharmacological inhibition studies show that PIN1 regulates key oncogenic pathways. Importantly, PIN1 promotes an immunosuppressive treatment-resistant tumor microenvironment and drives chemotherapy-resistance by inducing degradation of the transporter (ENT1) for the chemotherapy drug gemcitabine that is frequently used in front-line treatment of pancreatic cancer. Hence, the development of PIN1 inhibitors could increase sensitivity of pancreatic cancer to both chemotherapy and immunotherapy. The laboratory of Dr. Pellecchia (UCR) has developed initial PIN1 inhibitors that have promising pharmacokinetic properties by using a drug discovery strategy based on a combination of biophysical methods including 1) medicinal chemistry 2) NMR spectroscopy, 3) X-ray crystallography (with Dr. Blaha, UCR) and 4) denaturation thermal shift measurements. This structure-based design approach was used to derive innovative covalent PIN1 targeting agents that cause degradation of PIN1 in pancreatic cancer cell lines. Guided by our resources and above preliminary data, this collaborative project between UCR and CoH will 1) optimize and 2) develop a potent and selective PIN1 inhibitor for treatment of pancreatic cancer. Aim 1 will design, synthetize, and iteratively optimize novel, drug-like PIN1 targeting agents. Aim 2 will study the mechanism of action and efficacy of most promising agents in cellular and animal models of pancreatic cancer. We will assess the pharmacokinetics properties (Dr. Horne and CoHCCC shared resources) of refined agents in mice and test their efficacy in animal models of pancreatic cancer (Dr. Horne, Dr. Raoof, CoHCCC), including orthotopic patient derived xenografts and transgenic mouse models of pancreatic cancer.
Pilot Research Projects
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Pilot #1 (Implementation of Therapeutic Trial) - Capacity Building Clinical Trial of Metformin Against Inflammation in Insulin-Resistant Breast Cancer Survivors of Hispanic and/or African Ancestry
Lead PI: Kendrick Davis, Ph.D.
Co-Lead: Victoria Seewaldt, M.D.
Co-Investigator: David Lo, M.D., Ph.D.Abstract
This pilot project will build capacity for the development of cancer health-relevant clinical trials at UCR. The project will develop a clinical trial at UCR involving a collaboration between UCR Lead scientists and scientists at City of Hope Comprehensive Cancer Center (CoHCCC). The project will employ state-of-the-art single-cell transcriptomics and ATACseq in the context of a simple therapeutic trial. This trial will test the ability of standard-of-care metformin to reduce inflammation in insulin-resistant breast cancer survivors. The trial will initially be conducted at CoHCCC using CoHCCC patients and IRB. In Year 3, the trial will be opened for accrual at UCR. Metformin is known to reverse insulin resistance and remove senescent cells. This capacity building trial will test in insulin-resistant Latina and African American/Black breast cancer survivors, the hypothesis that metformin can 1) restore metabolic health (reverse insulin-resistance), 2) reduce chromatin acetylation and opening at specific genes (e.g., for IL6, TNFα and/or INFβ), and 3) reduce inflammation and circulating senescent cells. The project will enhance UCR clinical-trials capacity by conducting a UCR-CoHCCC partnered trial at CoHCCC in a diverse cohort and will provide capacity building in biospecimen collection and biomarker analysis. To assess medical adherence, body image and satisfaction with appearance after cancer treatment, as well as, social determinants of health, nutrition and food shopping, food security, and physical activity habits, we are using emoji-based measures. Emoji are expected to increase response rates, decrease cognitive load, and have universal appeal. However, psychometrics associated with validating these claims are forth coming. Hence, we will be building upon an ongoing series of psychometric studies that look to establish the validity of emoji measures in health and mental health.
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Pilot #2 - Control of Protein Synthesis by eIF4A1 and mRNA m6A Modification in Acute Myeloid Leukemia
Lead PI: Seán O’Leary, Ph.D.
Co-Lead: Rui Su, Ph.D.Abstract
Cancer cells require sustained high levels of protein synthesis for oncogenesis and disease progression. To achieve this, the cellular protein synthesis (“translation”) machinery is dysregulated to facilitate the biochemical and physiological demands of cancer cells. Acute myeloid leukemia (AML) is a common and fatal hematopoietic malignancy. Despite improved therapeutic options, over 70% of AML patients cannot survive beyond 5 years. This underscores a critical need for more effective approaches to treat AML. Emerging evidence indicates that aberrant translation is a hallmark of leukemia and targeting mRNA translation represents a promising strategy to combat AML. Translation initiation factor 4F (eIF4F) is a heterotrimeric protein complex, including a cap-binding subunit eIF4E, an RNA-binding/scaffolding subunit eIF4G, and a DEAD-box RNA helicase eIF4A. eIF4F recognizes the mRNA 5ʹ cap, enabling mRNA recruitment to the ribosome. The eIF4F complex activity significantly increases in cancer, including in leukemia, and has been recognized as an important driver of oncogenesis and a major cancer chemotherapeutic target. Inhibitors of all its subunits have offered significant promise as anticancer agents. N6-Methyladenosine (m6A), the most prevalent modification in mRNAs, plays a fundamental role in regulating mRNA translation, and increasing evidence suggests that its dysregulation might lead to oncogenesis. How m6A modifications regulate translation of specific mRNAs remains poorly understood and it remains largely unexplored whether m6A-mediated cap-dependent translation involves eIF4F subunits. Our preliminary observations indicate that eIF4A1, a key eIF4F subunit, interacts with the m6A machinery and is aberrantly highly expressed in AML patients. Based on our preliminary data this project tests the hypothesis that targeted m6A 5ʹ-leader/mRNA modification perturbs eIF4F function to promote oncogenic translational deregulation in AML. The project involves an integrated in-vivo and in-vitro study that comprehensively quantifies the impact of mRNA m6A modification on eIF4A1/eIF4F function, from single-molecule level, through in-vitro biochemistry, to the realm of cellular and animal physiology. Specifically, Aim 1 will define the role of eIF4A1 in AML pathogenesis; and Aim 2 will dissect the biochemical impact(s) of mRNA m6A and its “reader” and “writer” proteins on eIF4A1/eIF4F function. Our studies will cultivate a diverse force of cancer biologists, especially those from underrepresented minority backgrounds to enhance diversity in cancer research.
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Pilot #3 - Utilizing RELM-alpha-/-(M2 Macrophage-Polarized) Mice to Develop Novel Desmoplastic Models and Targeted Therapies for Pancreatic Cancer
Lead PI: Meera G. Nair, Ph.D.
Co-Lead: Edwin R. Manuel, Ph.D.Abstract
Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second-leading cause of cancer-related death by 2030. Desmoplasia, or fibrosis, is a hallmark of the PDAC tumor microenvironment (TME) and is comprised of a dense extracellular matrix (ECM) containing copious amounts of hyaluronic acid and collagens. Desmoplasia negatively affects prognosis because it: 1) acts as a biophysical barrier to therapy, 2) increases interstitial fluidic pressure leading to blood vessel compression and 3) initiates signal cascades that suppress immunity and promote invasiveness. Biochemical cues initiated by the TME ultimately contribute to proliferation, migration, invasion, angiogenesis and apoptotic resistance. Effective methods to overcome desmoplasia in PDAC, in order to improve drug delivery and efficacy, continues to be a significant unmet need. Development of novel models that physiologically recapitulate fibrosis in human PDAC would accelerate evaluation of ECM-targeting strategies. According to the National Cancer Institute SEER data, pancreatic cancer disproportionately affects African Americans, resulting in higher incidence and lower survival rates compared to Caucasians. Bearing in mind differences in socio-economic status, education, and access to healthcare, several studies suggest there exist significant differences in the TME of African Americans that facilitate earlier onset of certain cancers and more aggressive tumor growth. Among these differences is a greater prevalence of tumor-associated macrophages (TAMs) that are primarily M2-polarized (pro-tumor). TAMs are one of the most abundant immune subsets in the PDAC stroma and promote fibrosis, tumorigenesis, immune escape, metastasis and therapeutic resistance. Strategies to eliminate or reprogram TAMs into a more M1 (anti-tumor) phenotype is currently an area of intense research.
In this project, we propose complementary studies that will leverage the expertise of Drs. Meera G. Nair (UCR) and Edwin R. Manuel (COH) to develop novel tools and therapies that will aid in minimizing desmoplasia and M2 TAMs in PDAC. This will include the development and characterization of more relevant, desmoplastic PDAC models utilizing a M2 macrophage-driven fibrosis mouse model developed by Dr. Nair (AIM 1) as well as TAM-targeting strategies developed by Dr. Manuel (AIM 2). The development of a clinically relevant PDAC model with M2 macrophage-driven fibrosis will be critical for identification of effective therapeutic interventions in future grant applications to counter health disparities observed for PDAC.