PI and Program Director:
Co-PI and Co-Program Director:
Progam Coordinator:
Training Oversight Committee (TOC): Ensures consistency and quality of training; and provides feedback on training content and advice on trainee recruitment strategies.
Postdoctoral Fellows Committee (PFC): Composed of current T32 Fellows and alumni. Provides feedback to the Co-Directors, Program Coordinator, and TOC on structure, content, and quality of training. Serves as liaison with the HMS Office of Postdoctoral Fellows. Selects faculty for T32 sponsored courses. Peer support for Cancer Neuroscience trainees.
External Advisory Board (EAB): Provides Program Administration with expertise and advice on scientific direction, trainee recruitment, diversity and community outreach.
The overarching goal of the Agar laboratory is to develop and implement mass spectrometry and optical imaging approaches for surgical pathology and oncology. Agar and her students also develop, validate, and apply imaging approaches for drug development and disease molecular classification for the practice of precision medicine (27, 28). Part of their research takes place in the Advanced Multimodality Image Guided Operating (AMIGO) suite which contains state-of-art laboratories for tissue culture and optical and mass spectrometry imaging. Their work on the real-time analysis of the onco-metabolite 2-HG to support surgical decision making (29) constitutes the basis for the first IRB-approved study to use mass spectrometry derived diagnostic information to support surgical decision making. Their efforts to improve the management of brain tumors include extensive imaging of targeted therapies to evaluate their permeability through the blood-brain barrier in pre-clinical animal models (30, 31) and clinical trial patients with correlation to non-invasive radiologic imaging (32) and detailed pharmacodynamics. They have also developed a metabolomics platform (33-35) with single cell resolution to investigate key details of brain cell energy metabolism, including its dynamic response to brain activity and how it varies among different cell types in the brain. Dr. Agar has collaborated extensively with other mentors on this training initiative (e.g., Drs Haas-Kogan, Ligon and Yellen).
The Anderson lab studies T cell responses in experimental models of inflammatory disease states, including central nervous system (CNS) autoimmunity and cancer (36-38). Through this research they have identified cellular and molecular mechanisms that regulate the T cell response and influence disease outcome. In the field of CNS autoimmunity, they have done seminal work on the development of the autoreactive T cell repertoire. In the cancer field, they have studied regulation of the CD8+ T cell response. Notable discoveries include (i) demonstration that the checkpoint receptor Tim-3 marks terminally exhausted CD8+ T cells in tumors, (ii) elucidation of the gene programs that underlie CD8+ T cell states in tumors, (iii) determination of how immune checkpoint receptors function in different immune cells to regulate anti-tumor immunity and (iv) discovery that TCF-1 is a key regulator of stem-like CD8+ T cells that are requisite for response to checkpoint blockade immunotherapy [e.g., (38-42)].
Ovidiu Andronesi’s laboratory focuses on developing in-vivo metabolic MR imaging of brain tumor patients. His lab develops acquisition and reconstruction methods for fast and high- resolution imaging (43) that can be applied in patients to map and type molecularly brain tumors pre-surgically, and to monitor longitudinally the treatment response. His lab performed pioneering work for non-invasive genotyping of IDH mutations in glioma patients (44) using in- vivo Magnetic Resonance Spectroscopic Imaging (MRSI), and recently his imaging methods were used to accelerate clinical translation and probe pharmacodynamics of novel targeted therapy with inhibitors of mutant IDH (45). Dr Andronesi’ lab has strong collaborations with clinical/translational partners on this training program including Dan Cahill, Tracy Batchelor, and Scott Plotkin and with industry partner Siemens Medical Solutions that manufactures clinical MR scanners.
Tracy Batchelor’s research focuses on targeted therapeutics for central nervous system malignancies [e.g., (46-50)]. He is Program Director for the DF/HCC P30/SPORE award, Targeted therapies for gliomas, which includes projects in both pediatric and adult gliomas and leads the Harvard/Stanford site in the U19 Glioblastoma Therapeutics Network. He has mentored over 100 trainees at multiple levels and was the previous Principal Investigator for an NCI-funded K12 clinical training grant for neuro oncologists. He has co-developed faculty members with Dr. Michael Greenberg and several M.D./Ph.D. neurology residents from his department trained as post-doctoral fellows in the HMS Department of Neurobiology.
Bradley Bernstein’s research focuses on epigenetics—changes in gene activity governed by influences outside the genes themselves—and specifically how modifications to the protein scaffold called chromatin contribute to mammalian development and human cancer. Bernstein’s laboratory is characterizing epigenetic mechanisms that underlie stem cells’ ability to give rise to almost any kind of cell and exploring how epigenetic mechanisms contribute to malignant transformation and tumor progression. His work is notable for the discovery of bivalent domains that poise developmental genes for alternate fates in stem cells (51), for the systematic identification of enhancer “switches” in the human genome that control cell type-specific gene activity (52), and for the characterization of epigenetic aberrations that lead to cancer (53-55).
Priscilla Brastianos and her trainees study molecular drivers of brain metastases towards identification of novel therapeutic targets. Their studies show branched evolution, in that all metastatic and primary sites shared a common ancestor yet continue to evolve independently (56, 57). In more than half of cases, they have found clinically actionable alterations in the brain metastases that are not detectable in the matched primary tumor. The Brastianos team also has a profile in malignant meningioma – the most common primary nervous system tumor. They led the study which demonstrated recurrent oncogenic alterations in AKT1 and SMO (58) - results which begin to define the spectrum of genetic alterations in meningiomas and identify potential therapeutic targets. In subsequent studies they have demonstrated additional potentially targetable alterations in meningiomas, including PIK3CA mutations and PD-L1 overexpression (59, 60), as well as alterations associated with progressive meningioma.
Daniel Cahill’s research has contributed key observations regarding the molecular mechanisms of chemoresistance in human glioblastomas, where combined radiation and alkylating chemotherapy temozolomide are the standard-of-care (61, 62). Cahill and his students have focused on the subgroup of gliomas characterized by IDH mutation and on targeted therapeutics for brain tumors (50, 63). Dr. Cahill has also participated in a broadly collaborative effort with Drs. Priscilla Brastianos on this T32 to characterize the molecular genetic alterations within multiple tumor types (craniopharyngioma, hemangioblastoma, spinal cord tumors, brain metastases, meningiomas, and others). Dr. Cahill has collaborated extensively with other T32 mentors on this application – specifically Drs Batchelor, Suva and Kaelin on the Glioma SPORE grant and on a recently awarded U19 Glioma Therapeutics Network initiative.
Antonio Chiocca’s laboratory is focused on malignant gliomas of the brain. Chiocca and his students have been researching how noncoding RNAs contribute to the pathobiology of this cancer (64). He has also been working on immunotherapy approaches, based on gene and oncolytic virus vaccine delivery (65). This has included preclinical screening but also clinical trials, where human specimens are interrogated after immunotherapy to determine the effects of the treatment perturbation (66). He co-leads a P01 grant on immunotherapeutic approaches to glioma. Recent studies under auspices of this P01 (with Drs Suva and Wucherpfennig on this T32 initiative) have culminated in an atlas of T cells in gliomas, highlighting CD161 and other NK cell receptors as immunotherapy targets (67).
The major goal of the Chiu laboratory is to determine the role of neural-immune interactions in pain, inflammation, and host defense. The Chiu laboratory utilizes interdisciplinary approaches to elucidate the crosstalk between the nervous system, microbes, and immune cells. Nociceptor neurons are specialized neurons that detect noxious/harmful stimuli. A major question in the Chiu lab is to understand how neurons sense microbial pathogens to regulate pain. Chiu and his students found that nociceptors directly detect bacterial pathogens to produce pain during infection (68-70). These neurons release mediators that impact the tissue surveillance and host defense functions of macrophage and neutrophils in the skin and respiratory tract (68, 70, 71). They have shown also that nociceptors directly regulate epithelial cells and microbiome composition in the gut to protect against infection (72).
William Curry focuses on antitumor immunity in patients with malignant brain tumors. Dr. Curry and his ream have initiated phase I clinical trials using immunotherapy approaches and, using clinical materials from these trials, performed detailed serological and tissue-based analyses of antitumor immune responses. One focus is on the discovery of novel glioma- associated antigens and monitoring antibody and T- lymphocyte responses to them as patients are treated (73, 74). More recently, Curry and his team have developed protocols and tools to enhance CAR T cell function in gliomas (75, 76). Dr. Curry has collaborated extensively with other mentors on this T32 including Drs Andronesi, Batchelor, Brastianos, Cahill, and Kaelin.
Lisa Goodrich and her trainees study neural circuitry of the auditory system. They have characterized cell types that make up these circuits using single cell RNA-sequencing and mouse genetics. They are studying a transcriptional network that drives auditory neuron development (77, 78) and characterizing the interactions among developing glia, afferent, and efferent axons that create orderly tonotopically organized bundles in the cochlea (79, 80). Their work on auditory circuit assembly intersects with cancer biology in two fundamentally important ways. First, they have been studying the mechanisms that preserve axon integrity in the cochlea in response to a range of traumatic events, including treatment with chemotherapeutic agents known to cause chemotherapy-induced peripheral neuropathy. Second, they study inner ear glia, which are unusually prone to form Schwannomas. By comparing inner ear glia to other peripheral glia, they can identify molecular differences that account for this vulnerability and might be exploited to prevent or treat Schwannomas. Dr.Goodrich is a long time collaborator with Dr. Segal on this T32.
Michael Greenberg and his students have defined molecular mechanisms of signal transduction that carry the neuronal activity-dependent signal from the membrane to the nucleus to activate gene transcription [e.g., (81-83). Building upon their signal transduction work, Greenberg and his colleagues are investigating how this experience-dependent process controls neural circuit development and plasticity (21, 84, 85). This work involves the integrated use of mouse models, traditional cell biological, biochemical, and electrophysiological methods, as well as next-generation sequencing technologies to analyze activity-dependent gene regulation and function. These studies seek to both elucidate the mechanisms by which neuronal activity shapes the development of the central nervous system and provide new insight into the etiology of various human cognitive disorders.
Chenghua Gu’s lab studies the cellular and physiological mechanisms underlying the unique neurovascular interactions of the blood-brain barrier and neurovascular coupling and works to harness new discoveries in this area for therapeutics. Her lab pioneered the investigation of the fundamental mechanisms underlying the communication between the nervous and vascular systems, including how neural and vascular networks are developed, how neural activity influences the development and function of the blood vessels that supply the brain, and how the blood-brain barrier forms and functions. One major breakthrough was the discovery that transcytosis regulation is a chief mechanism for blood brain barrier function (86- 88). More recent work has addressed neurovascular coupling – how does neural activity increase local blood flow to meet moment-to-moment changes in regional brain energy demand (89)?
Daphne Haas-Kogan has a broad background in molecular analyses of cellular responses to radiation and chemotherapy, with training and expertise in key research areas relevant to this proposed training program in Cancer Neuroscience. She has characterized pathways that underlie resistance of brain tumors to standard treatments [e.g., (90)] and has studied signaling pathways in gliomas, including inhibitors that target elements within these pathways (91, 92).
She has been the principal investigator and co-investigator on clinical trials testing molecular therapeutics and radiation therapy in pediatric malignancies. As a translational scientist, she has taken findings from her laboratory and used them to design clinical trials for adults and children with cancer [e.g., (93)]. She successfully carried out laboratory research, designed clinical trials [e.g., (94)], and established a robust clinical practice in radiation oncology, focusing on adult and pediatric brain tumors.
Rakesh Jain and his trainees treat solid tumors as complex organs, and not just a collection of cancer cells. To unravel the complex pathophysiology of this aberrant organ, they have developed or adapted an array of innovative animal models and novel technologies. These include genetically engineered mice with live reporters, transparent windows to visualize biological events in tumors growing in various organs, cutting-edge imaging technologies (e.g., multi-photon intravital microscopy, second-harmonic generation microscopy, optical frequency domain imaging, wide-field endoscopy, and quantum dot nanotechnology), and a novel genetic method to trace the origins of metastases. To date, Dr. Jain has trained more than 200 predoctoral and postdoctoral fellows. Representative publications from the Jain lab are as follows (47, 95-98).
William Kaelin and his trainees use biochemical, cell-based, and animal-based assays to shed light how cancer-relevant proteins regulate tumor growth. Their work on pVHL showed that deregulation of HIF2α, and HIF-target genes such as VEGF, plays a critical role in kidney cancer (99, 100). This information motivated the successful clinical testing of VEGF inhibitors for this disease. During studies, on pVHL, they also discovered how the stability of HIF (hypoxia- inducible factor) is coupled to oxygen availability. Specifically, they showed that the HIFα subunit of the HIF heterodimer undergoes an oxygen-dependent posttranslational modification, prolyl hydroxylation, which targets it for polyubiquitylation by pVHL and subsequent proteasomal degradation (101, 102). This helped to motivate the development of HIF2 inhibitors that are now entering in clinical trials (103). Most recently they applied their knowledge of 2-OG-dependent dioxygenases to the study of tumor-derived IDH mutant gliomas, which overproduce 2- hydroxyglutarate (2-HG). They have identified druggable targets of 2-HG which show promise in early clinical trials (104).
Vijay Kuchroo’s group focuses on understanding the molecular pathways and mechanisms leading to the dysregulation of the immune system in inflammatory diseases. More specifically, their work focuses on understanding the pathogenic mechanisms of autoimmune diseases and role of Tim-3 and other “checkpoint” molecules in regulating anti-tumor immunity. The laboratory discovered TIM-3 and TIM family of genes about 15 years ago (105). The role of Tim-3 in inducing T cell exhaustion and in regulating anti-tumor immunity has now been well- established [e.g., (106)] and has formed the basis for at least 8 different clinical trials for cancer. The laboratory also contributed to the discovery of Th17 cells and their role in inducing tissue inflammation and autoimmunity (107, 108) which formed basis for many of the anti-IL-17 based therapies. Dr. Kuchroo has mentored over fifty students and research fellows, many of whom have gone on to have stellar careers.
Keith Ligon’s laboratory studies adult and pediatric gliomas and with emphasis on molecular mechanisms that underlie resistance to therapy, e.g., (32, 109). He has led translational efforts and clinical trials at the National and International level including within the NCI Alliance for Clinical Trials neurooncology committee and Children’s Oncology group where he helps to lead and train pathologists in conduct of clinical trials and correlative science. He also co-leads the Broad-DFCI models center within the NCI Human Models Initiative - an international effort to make more than 1000 next generation cancer cell lines. Dr Ligon has collaborated with multiple mentors on this training program including Tracy Batchelor, Mariella Filbin, and Mario Suva.
The three main areas of interest for the Polyak lab are: (1) how to accurately predict breast cancer risk and prevent breast cancer initiation or progression from in situ to invasive disease (110), (2) better understand drivers of tumor evolution with special emphasis on metastatic progression and therapeutic resistance (111, 112), and (3) novel therapeutic targets in breast cancer with particular focus on cancers that are not effectively treated with current therapies including triple-negative breast cancer (TNBC) and inflammatory breast cancers (113, 114). Directly relevant to the cancer neuroscience program is the lab’s interest in brain metastases of breast cancer and their finding of striking similarities between poorly differentiated TNBC and rhabdoid tumors, potentially driven by common transcription factors (Jovanovic et al. in preparation). They have been investigating how the special metabolic state and microenvironment of the brain favors the outgrowth of subsets of breast cancer cells and promotes therapeutic resistance.
Francisco Quintana’s research investigates signaling pathways that control the immune response and neurodegeneration, with the goal of identifying novel therapeutic targets and biomarkers for immune-mediated disorders. Quintana and his team identified AHR as an important regulator of effector and regulatory T cells, and consequently autoimmunity (115). AHR is activated by environmental pollutants and small molecules provided by the diet, the commensal flora, and the metabolism. Thus, these studies identified molecular mechanisms by which environmental factors regulate the immune response (116). More recently the Quintana lab had focused on control of the innate immune response and on the role of astrocytes in control of immune function in the brain (117-119).
In the first few years of life, humans tremendously expand their behavioral repertoire and gain the ability to engage in complex, learned, and reward-driven actions. Similarly, within a few weeks after birth mice can perform sophisticated spatial navigation, forage independently for food, and engage in reward reinforcement learning. The Sabatini laboratory seeks to uncover the mechanisms of synapse and circuit plasticity that permit new behaviors to be learned and refined. They are interested in the developmental changes that occur after birth that make learning possible as well as in the circuit changes that are triggered by the process of learning. To conduct these studies, Dr. Sabatini’s laboratory creates new optical and chemical tools to observe and manipulate the biochemical signaling associated with synapse function. A few representative publications are as follows: (120-124).
Rosalind Segal’s lab has defined roles of the microenvironment in Shh-dependent development and tumor growth (22, 125-127). These contributions have enabled new clinical trials for brain tumors. More recently, the lab identified the anti-apoptotic protein Bclw as a Nerve Growth Factor (NGF)-regulated protein and a critical component of a localized axonal survival pathway (128). This work showed that transport and localized translation of bclw in axons are impaired during axon degeneration (19, 129), leading to the therapeutic approaches to mimic Bclw and prevent this degenerative process (130). These findings have uncovered molecular insights into Chemotherapy-Induced Peripheral Neuropathy (CIPN), and more recent efforts are also focused on understanding the metabolic basis of altered axonal health in CIPN. Dr. Segal has collaborated with Drs. Greenberg, Filbin, Ligon and Zhao.
Beth Stevens’ laboratory focuses on understanding how neural-immune interactions in the brain sculpt synapses during normal development and disease. Dr. Stevens and her students discovered that microglia, the brain’s resident immune cells, prune neural connections in response to signals from the classical complement pathway, a branch of the immune system (131-133). They uncovered a diverse set of immune molecules that regulate this process in the brain during normal development, providing insights into the pathological synapse loss of Alzheimer’s disease, dementia, and schizophrenia (134-136). Building upon this work, they have pioneered new approaches to image and quantify synaptic remodeling in health and disease models using a combination of high-resolution imaging, neuroanatomical, and electrophysiological approaches (137).
Mario Suva’s laboratory studies the biology of pediatric and adult gliomas with single- cell genomic technologies (23-25, 138). His lab leverages a systems biology approach to characterize and target the cellular states that drive gliomas (26). His studies have also refined our understanding of the composition of the tumor micro-environment in gliomas, with important therapeutic implications (4). Dr Suva’s lab has established and ongoing collaborations with Brad Bernstein, Priscilla Brastianos, Dan Cahill, Antonio Chiocca, Mariella Filbin, Rakesh Jain, Keith Ligon, Humsa Venkatesh and Kai Wucherpfennig.
Kai Wucherpfennig studies T cell immunology and has extensive expertise on the mechanisms of T cell receptor recognition, signaling and function e.g., (139-141). Most recently, his lab leveraged single-cell RNA sequencing (RNA-seq) to chart the gene expression and clonal landscape of tumor-infiltrating T cells across 31 patients with isocitrate dehydrogenase (IDH) wild-type and IDH mutant glioma. They identified potential effectors of anti-tumor immunity in subsets of T cells and identified the NK gene KLRB1 (encoding CD161) as a candidate inhibitory receptor. Genetic inactivation of KLRB1 or antibody-mediated CD161 blockade enhanced T cell-mediated killing of glioma cells in vitro and their anti-tumor function in vivo (67).
Gary Yellen’s laboratory studies the transient Warburg-like metabolic changes in brain cells that occur when neurons are stimulated, as well as the crosstalk between cellular brain metabolism and brain excitability (142). The lab develops novel genetically encoded fluorescent biosensors of metabolism and employs them to monitor metabolism in living brain tissue, in vivo and ex vivo, using two-photon fluorescence lifetime imaging (143, 144). In collaboration with Nathalie Agar’s lab, the Yellen lab uses mass spectrometry imaging of brain slices to learn the full response of cellular metabolic pathways in both health and disease.
Dr. Zhao’s lab has long-standing interests in characterizing and targeting oncogenic signaling pathways in cancer. She has characterized functional distinctions in PI3K isoforms (145-148) and developed first-in-kind “gain-of-function” kinase libraries that have led to identification of new kinases involved in tumorigenesis (149, 150). Most recently, the lab has investigated strategies to overcome drug resistance by combining targeted therapy and immunotherapies (151, 152). Dr. Zhao has had productive collaborations with many other faculty on this T32, including Drs. Polyak, Segal, Haas-Kogan and Ligon.
Mariella Filbin studies lethal high-grade gliomas of childhood including DIPG (23) and malignant embryonal brain tumors (24) that are in greatest need of therapeutic improvements. Through single cell genomics, Dr. Filbin has identified developmental and cellular contexts in which tumorigenic mutations shape the cellular hierarchy of the resulting tumors. This developmental “fingerprint” can then be used to design novel therapies that either enable differentiation of tumor cells, so they are no longer proliferating or induce tumor cell death (138). In the lab’s studies they are combining single-cell genetics and transcriptomics with gene editing, epigenetic, stem cell and pharmacologic methods to identify cellular states, hierarchies and networks underlying tumorigenesis, with the goal of establishing new druggable targets. Dr. Filbin collaborates extensively with Drs Haas-Kogan, Ligon, Plotkin, Segal, Suva, and Venkatesh on this training grant application.
Humsa Venkatesh works at the interface of neuroscience and cancer biology a to create a novel perspective on the neural regulation of cancers. As a postdoctoral trainee with Michelle Monje at Stanford she showed that bioelectric activity of neurons promotes glioma growth (3), identified a microenvironmental therapeutic target which, when inhibited, stagnates glioma growth in vivo (5) and defined microanatomical features of the neuron:glioma interface that enable this pathobiological relationship (4). Indeed, this body of work largely created the field of Cancer Neuroscience. Going forward Dr. Venkatesh aims to build her academic career on the development of this novel field studying microenvironmental neuron:cancer interactions & harnessing these dependencies for treatment.
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