Investigators

Summary

I am a physician scientist in radiation oncology with a focus on identifying targetable mechanisms of pancreatic cancer resistance in the laboratory, and dose escalated hypofractionated radiation therapy in the clinic. Over the course of my education and training, I have developed the expertise and skills to pursue my primary goal of identifying and solving research problems whose solutions can bring increased quantity and quality of life to my patients. I have a broad range of medical and scientific experience, and have been the most fulfilled when answering questions that could have a clear impact on the lives of patients I have met over the course of my career.
My primary long term research interests lie in the study of therapeutic resistance in cancer, and the discovery of targetable mechanisms by which response to cancer therapies can be enhanced. My postdoctoral and now current laboratory focus is on the interplay of stromal signaling with therapeutic resistance and metastasis in pancreatic cancer, and how the tumor microenvironment changes in response to radiation therapy. These interactions can dramatically affect the response radiation therapy and targeting them has the potential to substantially alter clinical outcomes. My lab utilizes orthotopic and metastatic mouse models to study the cellular and intracellular mechanisms of radiation sensitivity and resistance, and the ensuing immune and tumor microenvironment response, with the goal of discovering new therapeutic targets to synergize with current treatment modalities. We are currently studying the role of alpha and gamma secretases in modulating paracrine stromal signaling, and the effect of inhibition of these protein complexes on tumor response to radiation therapy. We are also investigating the impact dysregulated lipid metabolism on the suppressive pancreatic cancer immune microenvironment. My goal is to develop novel combination therapies to be brought back to the clinic, improving responses to therapy and overall clinical outcomes. 
Recent and Ongoing Projects: The role of ADAM10 in driving fibrosis and therapeutic resistance in pancreatic ductal adenocarcinoma: My postdoctoral research in the lab of Sana Karam, and the primary current focus of my lab is studying mechanisms of stromal crosstalk, fibrosis and immune infiltration in the PDAC tumor microenvironment. We identified through TCGA analysis that low expression of both EphrinB2 and ADAM10 confers an excellent prognosis, but overexpression of either leads to poor clinical outcomes. Through RNA sequencing analysis of PDAC tumors prior to treatment with neoadjuvant SBRT we found that high expression of ADAM10 and EphrinB2 was a poor prognostic sign in this cohort. We also found in orthotopic mouse tumors that ADAM10 expression was upregulated following RT. We hypothesized that induction of ADAM10 in response to cytotoxic therapies can lead to activation of the EphB4/EphrinB2 complex resulting in increased fibrosis, then driving aggressive tumor biology and resistance to cytotoxic therapies. We found that EphrinB2 cleavage produces a detectable biomarker of radiation induced fibrosis in patient plasma samples after treatment with SBRT. We also found that pharmacologic inhibition of ADAM10 abrogates radiation induced fibrosis in mouse tumors and enhances tumor killing by RT. By knocking out ADAM10 in tumor cells we dramatically altered the tumor proteome following RT, blocking induction of fibrotic matrisome protein expression, and leading to substantial increase in the efficacy of RT in orthotopic and metastatic models. My lab continues to study the impact of ADAM10 on tumor fibrosis, EMT and metastasis through its downstream targets, with the goal of developing therapeutic strategies targeting these pathways. This work was funded by grants from the RSNA and Cancer League of Colorado, and resulted in a first author publication in Cancer Research. 
Tumor fibrosis and immunosuppression through tumor cell activation of fibroblast notch signaling:
We are currently investigating multiple mechanisms of tumor-stromal crosstalk and how manipulation of these interactions can alter tumor sensitivity to radiation and cytotoxic therapies, as well as facilitate a more permissive tumor microenvironment to allow for anti-tumor immune responses. Stromal activation and fibrosis contributes heavily to immune suppression in PDAC by preventing immune cell infiltration and promoting suppressive polarization of macrophages, lymphocytes and MDSCs. Another key downstream target of ADAM10 cleavage involved in fibrosis and EMT is the Notch pathway. Notch is key mediator of cell surface signaling, and requires cleavage by ADAM10 and the gamma secretase complex to translocate to the nucleus and activate transcription. Notch is involved in many aspects of development and is dysregulated in KRAS driven malignancies like PDAC, impacting tumor cell survival, migration, invasion as well as stromal activation and immune cell polarization. 
We have found that blocking Notch cleavage through gamma secretase inhibition can dramatically sensitize syngeneic orthotopic tumors in vivo to radiation therapy, though this effect is much less significant in vitro. We have also found that PDAC tumor cells can activate notch signaling in fibroblasts in vitro, which is abrogated by gamma secretase inhibition. We are currently investigating the effects of genetic and pharmacologic manipulation of notch processing on tumor cells, fibroblast and immune cells within the tumor microenvironment. We hypothesize that tumor cells promote mesenchymal notch signaling, leading to fibrosis and immunosuppression within the tumor microenvironment. We are testing whether the clinically available gamma secretase inhibitor nirogacestat can enhance tumor response to radiotherapy and immunotherapy by blocking myofibroblast activation and stromal fibrosis. This project has been funded by the RSNA Research Scholar Grant, and is currently funded by ACS Clinician Scientist Development Grant CSDG-22-119-01-ET (2023-2027). This work was selected for an oral presentation at the 2023 ASTRO conference and a manuscript is in preparation. 
Tumor cell orchestration of TME immunosuppression through lipogenesis and recruitment of ApoE:
Our other main focus is the role of tumor cell orchestration of immunosuppression through metabolic manipulation of the tumor microenvironment. We are investigating mechanisms by which PDAC tumor cell lipogenesis promotes macrophage infiltration and suppressive polarization, preventing activation of an antitumor immune response. We found that one of the most overexpressed proteins in the microenvironment of mouse and human PDAC tumors is the lipoprotein ApoE. ApoE is a crucial protector against atherosclerosis as well as Alzheimer’s disease. ApoE is a key mediator of cholesterol metabolism, present in a variety of lipoprotein particles. Knockout or mutation of ApoE can lead to accelerated atherosclerosis as well as development of B-amyloid plaques. ApoE secretion in atherosclerotic plaques promotes M2 macrophage polarization, preventing an autoimmune response, promoting plaque regression and fibrosis. 
PDAC tumor cells have large alterations in their lipid metabolism, overexpressing the enzymes mediating lipogenesis, greatly upregulating fatty acid synthesis downstream of glycolysis. RT has been shown to oxidize lipid particles, as well as elevate lipid levels in normal tissues for weeks following exposure. By mass spectrometry analysis, we found that ApoE expression in the PDAC TME is increased by high dose RT in a manner dependent on ADAM10. We have also found that neoadjuvant SBRT leads to an upregulation in ApoE in patient tumor samples, in addition to a downregulation of the LDL receptor, which binds ApoE containing lipid particles. 
We hypothesize that de novo tumor lipid synthesis serves to recruit macrophages, which secrete ApoE to incorporate these excess lipids into lipoprotein particles, promoting M2 macrophage polarization, immunosuppression, and fibrosis. We further hypothesize that RT enhances this lipid synthesis, recruiting ApoE expressing macrophages, resulting in the late treatment effects of fibrosis and immunosuppression. This could represent a novel and targetable mechanism by which through lipogenesis PDAC co-opts physiologic atheroprotective immunosuppression to foster a cold immune microenvironment. Targeting tumor lipogenesis in conjunction with tumor-directed RT has potential to enhance the immunostimulatory effects of RT while mitigating its immunosuppressive and pro-fibrotic effects. We are currently further testing these hypotheses to examine the impact of modulating lipogenesis and ApoE expression on response to radiation as well as immunotherapy.