Current projects in the lab include:
• Understanding the function of mutant p53 in epithelial cancers
• Deciphering how standard chemotherapies modulate tumor immune response in combination with checkpoint immunotherapy.
• Determining mechanisms of immune-modulation in metastatic TNBC subtypes
Understanding the function of mutant p53 in epithelial cancers
The mutation of TP53 is one of the most frequent genomic alterations in human tumors. p53 is mutated in over half of cancers, including over 90% of triple-negative breast cancers. TP53 encodes p53, a sequence-specific transcription factor that regulates expression of genes involved in numerous cellular processes, including maintenance of genome stability. Mutations in p53 are frequently single amino acid missense mutations in residues that directly contact DNA or alter the structure of the DNA-binding domain. In addition, several missense mutations occur with high-frequency in “hot spot” residues. In addition to losing tumor-suppressive function, these mutations encode mutant p53 proteins proposed to acquire gain-of-function (GOF) activity, leading to novel oncogenic phenotypes. We have used CRISPR/Cas9-mediated gene editing to generate mutations in TP53 in corresponding p53 hotspot mutations. These models provide the framework for understanding cellular adaption and temporal changes associated with loss of p53 function.
Deciphering how standard chemotherapies modulate tumor immune response in combination with checkpoint immunotherapy
Triple-negative breast cancer (TNBC) is one of the most aggressive types of breast cancer. TNBC affects younger women and accounts for over 25% of all breast cancer deaths due to more frequent metastasis and shorter survival outcomes when compared to other breast cancer subtypes. Prognosis is especially dismal for metastatic TNBC, with 50% mortality within one year of diagnosis. Development of targeted therapies for TNBC is challenging due to molecular heterogeneity and a lack of high-frequency “driver” alterations within patient tumors.
Cancer immunotherapies that target the immune-suppressive pathways are a paradigm shift in treating patients with metastatic cancers in terms of lives saved and years restored. Recently, immune checkpoint inhibitors (ICIs) targeting PD1/PD-L1 have improved survival in TNBC and have received FDA approval to treat metastatic TNBC in combination with nab-paclitaxel. However, only a subset of patients respond to ICIs and increased overall survival benefit is limited to patients with PD-L1 expression. Therefore, there is a critical need to understand mechanisms of immune suppression in immune cold TNBCs and identify additional treatment strategies for PD-L1 negative metastatic TNBC patients unresponsive to immunotherapy.
As part of an NCI-funded Vanderbilt Breast SPORE (https://www.vicc.org/research/breast-spore), we utilize both syngeneic murine tumor models and biospecimens from patients enrolled on a clinical trial evaluating carboplatin alone or in combination with anti-PDL1 to investigate mechanisms of resistance to ICI and the differential effects on intra-tumor and circulating immune cells. An additional focus of research is the evaluation of novel gene rearrangements with immune regulatory function in TNBC.
To determine mechanisms of immune-modulation in metastatic TNBC subtypes
Despite having high mutation loads and patterns of genomic instability, mesenchymal TNBCs are characterized by an absence of immune cells within the tumor. Using global DNA methylation analysis, we demonstrate that while mesenchymal tumors have overall increased global hypomethylation, there is hypermethylation in promoter regions near genes know to be repressed by the polycomb repressor complex 2 (PRC2) and involved in interferon response and MHC-I antigen processing and presentation pathways. Therefore, mesenchymal TNBCs may have developed mechanisms to escape immune surveillance through selective repression of antigen presentation. We are currently determining the mechanism by which the PRC2 complex activity leads to repression of antigen presentation and evaluating the efficacy of EZH2 inhibitors in combination with chemotherapy or immunotherapy in syngeneic mouse models. Working with a multi-disciplinary team of basic, translational, and clinical investigators, the ultimate goal is to generate preclinical results that can be rapidly advanced in early-phase clinical trials and extend the lives of metastatic TNBC patients.