CURRENT

Aubrey Michi, Ph.D.

Aubrey earned her Ph.D. in Respiratory Medicine from the University of Calgary in 2021. She joined the lab of Dr. Bruce Spiegelman where her research focuses on expanding the repertoire of phosphocreatine functions beyond its established ATP buffering and thermogenic roles. The prevailing paradigm is that most or all cellular enzymes, or protein kinases, utilize ATP for protein phosphorylation. However, phosphocreatine is also an abundant high-energy phosphate which has a phosphate group that makes an energetically favorable leaving group. Aubrey is currently working to identify novel protein kinases that utilize phosphocreatine as a high energy phosphate donor for protein phosphorylation and the biological implications of phosphocreatine-dependent kinase phosphorylation. Using quantitative mass spectrometry and phosphoproteomics, Aubrey has identified numerous mitogen-activated protein kinases (MAPK) that undergo phosphocreatine-dependent phosphorylation. As aberrant MAPK signaling is a hallmark of many cancers, alternative mechanisms driving MAPK signaling may contribute to altered cell proliferation and metastasis. Aubrey joined the CCBM T32 program to obtain the scientific training and career development experiences to achieve her goal of independent investigator studying metabolism and viral infections.

Zachary Sandusky, Ph.D.

Zachary earned his PhD from Vanderbilt University in 2020. He then joined the laboratory of Dr. Myles Brown, where he studies targeted protein degradation of the transcription factor, estrogen receptor alpha (ER) in ER+ breast cancer. His research seeks to better understand the mechanism of action for selective estrogen receptor degraders (SERDs), a new class of ER antagonists that target ER protein for degradation via the ubiquitin-proteasome pathway. Utilizing a functional, genome-wide, CRISPR/Cas9 screening approach, Zachary has identified ubiquitin-proteasome genes that are required for sensitivity to SERDs. He is interested in determining if loss of these ubiquitin-proteasome pathway genes is a mechanism for ER+ breast cancer to develop SERD resistance. Furthermore, Zachary will use his screening approach to identify new therapeutic targets in SERD-resistant ER+ breast cancer. Zachary joined the CCBM T32 training program to prepare for a career as an independent researcher in the fields of oncology and pharmacology. The program will provide essential training support, mentoring, and professional experiences that will supplement his laboratory research and enhance his development as a scientist.

Chelsey LeBlang, Ph.D.

Chelsey earned her Ph.D. in Anatomy & Neurobiology at Boston University School of Medicine in 2020.  She joined the lab of Dr. Rosalind Segal in 2021, where she is working to characterize molecular mechanisms underlying axonal degeneration in Chemotherapy Induced Peripheral Neuropathy (CIPN). The Segal Lab has recently described two pathways resulting in calpain-mediated axonopathy in rodent models of CIPN; one due to reduction of axonal bclw protein and the other through the activation of the NAD-ase, SARM1. The goal of Chelsey’s project is to validate the relevance of these pathways in the pathogenesis of human CIPN using a novel human induced sensory neuron model. To assess the effects of chemotherapy treatment on axonal degeneration, she will quantify changes in axonal morphology, calcium flux, bclw and SARM1 protein localization and concentration, calpain activity, and SARM1 metabolite production. She will then test the efficacy of bclw protein mimetic and SARM1 inhibitor treatments previously shown to have a rescue effect in rodent models of CIPN. Chelsey joined the CCBM T32 program to gain the guidance and mentorship needed to complete these metabolomic and chemoproteomic studies, and to attain academic training in the field of cancer chemical biology, which she has not had, due to primary experience in neurobiology. The training she receives in the CCBM T32 program will assist in her goal to identify therapeutic targets in nervous system and immune disorders as an independent researcher.

Mona Sharafi, PhD

Mona earned her PhD from the University of Vermont in 2019. She joined the lab of Dr. Sara Buhrlage in 2021 where she works on the development of highly potent and selective ubiquitin specific protease 28 (USP28) inhibitors by a combined synthetic and computational approach. To advance the deubiquitinating enzyme (DUB) field, the Buhrlage lab has launched a comprehensive campaign to develop reversible and covalent small molecules that target DUB catalytic as well as non-catalytic pockets. However, to date, only a few USP28 small molecule ligands have been reported and shown to promote degradation of c-Myc supporting the notion that pharmacological inhibition of USP28 is a potential novel therapeutic strategy for drugging Myc. Selectivity expected of high-quality probe compounds and a lack of a complex crystal structures has hampered optimization efforts. Therefore, the primary focus of her project is to develop potent and selective inhibitors of USP28. In addition, she will pursue expansion of separate reagents to support target validation studies and leverage the compounds toward other DUB enzymes. T32 training, not only will provide the opportunity to pursue her research and address important challenges in the field but also enhance her mentorship, grantsmanship and technical skills which will position her for a successful career in teaching and independent academic research.

Conor Ronayne, PhD

Conor earned his PhD from the University of Minnesota in 2020. Shortly after, he joined the lab of Pere Puigserver where he studies mechanisms of cell death and cell survival in mitochondrial diseases (MDs). The mitochondria, largely responsible for maintenance of energy, biosynthesis, and redox status, also play important roles in signaling. Hence, defective mitochondrial function has pleiotropic effects in cellular physiology, where mutations in mitochondrial genes can manifest disease phenotypes. Currently, treatment options are limited for patients with MD due to a limited molecular understanding of the disease. In this regard, the Puigserver lab recently identified that inhibition of mitochondrial protein synthesis with tetracyclins rescues mitochondrial disease cells from nutrient deprivation, and delays disease progression in a mouse model of MD. Conor’s project, using biochemical, genetic, and proteomic approaches, seeks to determine the precise mechanism of action toward signaling pathways that initiate at the mitochondrial ribosome upon tetracycline treatment.  Conor joined the CCBM T32 training program to gain training in science and career development toward his goal of establishing his own research lab to study metabolism, disease, and therapy.

Erika Portero, PhD

Erika earned her Ph.D. in Chemistry from University of Maryland in 2020. She joined the lab of Dr. Nika Danial where she will investigate the contribution of metabolic alterations to the growth of low-grade gliomas (PLGAs) — the most common brain tumors in children. Many PLGAs go through a relapsing/remitting disease course with major adverse effects on brain development and function. Thus, targeted therapies with reduced neurotoxicity are highly desired. Erika will apply small molecule mass spectrometry approaches to characterize metabolic profiles associated with two prominent BRAF oncogenic drivers in PLGAs. Erika’s research will combine analytical chemistry and biochemical tools to comprehensively map and functionalize metabolic distinctions associated with these oncogenic drivers in order to define actionable metabolic vulnerabilities. She joined the CCBM T32 training program to gain the academic and professional training needed to attain her goal of becoming an independent scientist.

Benjamin Chandler, PhD

Ben earned his PhD from the University of Michigan in 2020. He joined the lab of Dr. William Kaelin where he is investigating the degradation of Forkhead Box A1 (FOXA1). FOXA1 is a pioneer transcription factor specifically essential in estrogen receptor-positive (ER+) breast cancer, making it an attractive therapeutic target. Although ER+ breast cancers are FOXA1-dependent, FOXA1 would not classically be viewed as a druggable target. Recent studies, however, have shown that some undruggable proteins can be targeted with drugs that directly or indirectly degrade them. Current efforts to screen for protein degraders rely heavily on so-called “down” assays that directly or indirectly measure the loss of the protein of interest (POI). Such down assays are limited by a low signal-to-noise ratio and a narrow dynamic range, resulting in a high false-positive rate. Using a gain of signal (or “up”) assay, previously developed in the Kaelin Lab, Ben will perform genetic and chemical screens to identify genetic mediators and pharmacologic compounds that degrade FOXA1. Ben joined the CCBM T32 training program to continue his scientific training in cancer biology and drug development. The additional training in chemical screening and focus on state-of-the-technologies will aid him in attaining his goal of becoming an independent scientist.

ALUMNI

Xiaofeng Zhang, PhD

Xiaofeng earned his PhD from the University of Massachusetts Boston in 2019. He joined the lab of Dr. Jun Qi where his research focuses on establishing biological rationales for hematologic malignancy therapy by using novel small molecules as chemical probes. Dysregulation of a master oncogene, the MYC transcription factor is implicated in the pathogenesis of multiple myeloma (MM).  Although dysregulation of MYC has been shown to transform cells in culture and to induce MM in transgenic mouse models, the mechanism by which aberrant MYC transcriptional program leads to MM in humans is not well understood. In collaboration with the Anderson laboratory, he investigated the consequences of selective knockdown of the histone lysine demethylase, KDM5A, a transcriptional activator of MYC target genes. Xiaofeng recently transitioned into a position in industry.

Narek Darabedian, PhD

Narek earned his PhD from the University of Southern California in 2019. He joined the lab of Dr. Ed Chouchani where he will investigate pharmacological approaches to treating obesity. Activation of calorie-burning (thermogenesis) in brown and beige adipose tissues (BAT) is protective against obesity and may also reduce obesity-related cancer risk. The Chouchani lab discovered that covalent modification of metabolic proteins can induce the calorie burning activity of this protein. In collaboration with Dr. Nathanael Gray, Narek will use a chemoproteomic platform to identify covalent scaffolds that target metabolic proteins. He expects to identify at least 20 scout molecules and will subsequently use structure activity relationship (SAR) optimization to generate potent and selective drug candidates. He will test candidates for effectiveness in mouse models and human adipocyte cell cultures. Narek joined the CCBM T32 program to get the training he needs to accomplish his research goals of treating obesity and to prepare him to be independent researcher studying a broad set of questions in metabolism and disease.

Kedar Puvar, PhD

Kedar earned his Ph.D. from Purdue University in 2020. He joined the lab of Dr. Eric Fischer, where he will be studying the structural basis of targeted protein degradation. This concept involves causing the destruction rather than inhibition of disease-causing proteins using small molecules that bring protein targets to E3 ubiquitin ligase enzymes that mark the protein for degradation. Kedar’s research will employ biochemical and structural techniques to further our understanding of these molecules. This will help us better understand the mechanisms the cell uses to carry out protein degradation, specifically the ubiquitin-proteasome system. Many known degraders exist whose mechanisms are not well understood, or whose 3D structures in complex with their ligases and protein targets are unknown. Identifying how new ubiquitin ligases that are recruited by degraders to tag target proteins for degradation will be of great interest to both biologists and medicinal chemists. Kedar joined the CCBM T32 program to gain the scientific and professional development training needed to set him up for success in an independent research career. Kedar was awarded an F32 postdoctoral fellowship in 2021, and transitioned into a role in industry in early 2022.

Matthew Streeter, PhD

Matt earned his PhD from Yale University in 2019. He joined the lab of Dr. Justin Kim where he aims to develop a platform for the discovery of macrocyclic peptide therapeutics. Macrocyclic peptides offer properties that bring to bear several key benefits of other therapeutic modalities. Similarly to small molecules, macrocyclic peptides can be optimized for cell-permeability and oral bioavailability, and similarly to antibody-based therapeutics, they can adhere to relatively flat and featureless protein surfaces. In combination, these properties make macrocyclic peptides ideal for therapeutic targets that are often recalcitrant to small-molecule- and antibody-based therapeutics, such as intracellular protein-protein interactions. Matt will begin construction of peptidic libraries containing homodetic peptides and move toward incorporation of synthetic, natural-product-inspired building blocks. With this large pool of amino acids, the generated libraries will achieve rapid structural diversity that is unparalleled within currently available peptide discovery platforms and should aid in achieving therapeutic endpoints. Matt joined the CCBM T32 training program to learn as much as he can during his time at DFCI while being a part of a great community of scholars. He is currently a Scientist in Discovery Chemistry at Entrata Therapeutics.

Laura Stevens, PhD

Laura earned her PhD from Yale University in 2017. She joined the lab of Dr. Kornelia Polyak  where she studies stromal-induced heterogeneity of tumors and epigenetic regulation in therapeutic resistance.  She has generated a reporter system that marks cancer cells that are in direct contact with stromal cells, facilitating the purification of these cells from bulk tumors and subsequent functional analyses. She will compare stroma-contact and no-contact cells to identify genes and pathways driven by spatial proximity to stroma and will test several hypotheses. These include the hypothesis that stroma can affect tumor cell phenotypic and epigenetic heterogeneity to promote the evolution of therapy resistant clones and the hypothesis that the stroma is regulating tumor cell epigenetics by altering the metabolome. Laura’s career goals include establishing her own lab, and she has joined the CCBM T32 training program to get the mentorship and career development to help her progress to an independent scientist. The program will expand her knowledge of scientific approaches and state-of-the-art technologies in cancer chemical biology and metabolism in support of her primary research interests. After completing her CCBM Training, Laura continues to conduct research in Polyak lab.

Jon Dempersmier, PhD

Jon earned his PhD from the University of Berkeley in 2015. He joined the lab of Dr. Hari Arthanari where he studies the structural basis of transcription factor sequence specificity and function.  Many transcription factors contain intrinsically disordered regions (IDRs), which are not amenable to structural analyses via X-ray crystallography or cryo EM.  These IDR regions also harbor mutations found in cancer, but the roles these regions play in normal cellular function and the roles cancer associated mutations play in disease are not understood. The Arthanari lab is a pioneer in the use of nuclear magnetic microscopy (NMR) for structural studies of IDRs, and Jon will be using the structural clues identified by NMR in a host of transcription factor IDRs to interrogate the roles of these regions. In addition he will be investigating the interaction of transcriptional activation domains (TADs) with the KIX domains of transcriptional mediators such as MED15.  These studies will inform small molecule drug design to address aberrant transcription factor activity in cancer cells.  Jon joined the CCBM T32 training program to prepare for a career as an independent investigator. The program will provide support, mentoring and exposure to state-of-the-art technologies and set him on a path toward developing a platform to interrogate transcription factors that he will use as the basis for the work of his own lab. Jon has completed his CCBM training and continues to conduct research in Arthanari lab.

Laura Stransky, PhD

Laura earned her PhD from Tuft University in 2017. She joined the lab of Dr. William Kaelin where she is investigating the molecular basis of heterogeneous dependence of clear cell renal carcinoma cells (ccRCC) on Hypoxia Inducible Factor (HIF)2 alpha in preclinical models and the clinic. Von Hippel-Lindau gene (VHL) inactivation is an early event in most cCRCC tumors. Loss of VHL leads to an accumulation of the alpha subunits of the HIF transcription factor, a master regulator of hypoxia-inducible genes and a driver of a pro-survival gene expression program. HIF2 alpha inhibitors show some effect against ccRCC, but the response is variable. Understanding the basis of the heterogeneous response will allow the development of predictive biomarkers of response and resistance and enable the design of strategies to circumvent resistance. Laura is developing mouse models and using CRISPR screens and molecular profiling to identify factors associated with HIF2 alpha dependence.  She joined the CCBM T32 training program to gain both scientific training and career development experiences essential to her goal of becoming an independent scientist leading her own research group in the study of cancer signaling. After completing her CCBM training, Laura continues to do research in the Kaelin lab.