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An NCI-designated Comprehensive Cancer Center, affiliated with the University of Pittsburgh School of Medicine
Research
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Cancer related research: 1. Tumor immune microenvironment in ovarian cancer focusing on tumor associated macrophages and TGF-B as well as strategies to enhance benefit of immunotherapy in ovarian cancer; 2. Her2 directed targeted therapy in combination approach targeting resistance mechanisms; 3. DNA-damage response targeted therapy based on ATR targeted therapy in combination approach to reverse PARPi resistance in ovarian cancer.
Dr. Phuong Mai’s work focuses on the role of genetic testing to identify individuals with a hereditary predisposition to cancers, including breast and ovarian cancer. She is also working on risk reducing interventions and early-detection in individuals at increased cancer risk.
Marcus Malek, MD, director of Pediatric Surgical Oncology at UPMC Children’s Hospital of Pittsburgh, directs a unique research program focused on improving surgical outcomes in pediatric tumors through use of novel molecular imaging technology. Towards this end, he and his lab team are developing new surgical tracers to guide surgeons to the tumor, facilitate safe resection, and confirm that the entire tumor was removed.
Complete surgical resection of tumors is critical to providing the best possible patient outcomes, but unfortunately, incomplete resection is a common occurrence. A significant program being pursued by Dr. Malek and his team is a dual-labeled, tumor-specific tracer, that will provide both visual and audible signals within the tumor that can be detected using existing surgical tools. Although the project is specifically targeting pediatric neuroblastoma and osteosarcoma, ultimately the technology can also be applied to other types of pediatric tumors.
My research focuses on studying the protein-protein interactions within the “CBM” signaling complex, composed of CARMA1 (a scaffolding protein), BCL10 (an adaptor protein), and MALT1 (a scaffolding protein with proteolytic activity). In normal lymphocytes, the CBM complex mediates activation of the pro-survival NF-kappaB transcription factor in response to antigen receptor stimulation. Inappropriate activation of this complex drives neoplastic diseases including lymphoid cancers such as non-Hodgkin Lymphoma and likely a subset of pediatric T-cell lymphoma. My goal is to understand how inhibiting protein-protein interactions within this complex alters the pathogenesis of these malignancies and to determine if inhibiting protein-protein interactions within the CBM complex represents a novel treatment strategy for a subset of patients with lymphoma.
I am interested in reducing health disparities through understanding the complex pathways socioeconomic status and stress affects cancer genomics and, subsequently population health. My current work focuses on neighborhood socioeconomic metrics that may influence head and neck cancer through the cancer care continuum. I aim to develop a case-control study with prospective follow-up of patients in Western Pennsylvania to elucidate this pathway in head and neck cancer.
Dr. McAuliffe focuses on the surgical treatment of all breast diseases, with special interest and research emphasis on invasive lobular breast cancer, de-implementing low-value breast surgical care, pre-invasive neoplasms such as DCIS and LCIS, premenopausal and elderly breast cancer, breast conservation therapy, locally advanced breast cancer and axillary management. She collaborates with the Breast Disease Research Repository for breast biospecimens and leads several breast surgery clinical trials.
My research interests are in the underlying causes of mobility disability in cancer survivors. Specifically, I am interested in investigating how neuromuscular and cognitive capacities change with cancer and treatment and how they are associated with changes in balance, gait, falls, and quality of life.
Our lab is exploring the role of the gut and tissue microbiome on systemic immunity in the context of complex diseases such as autoimmunity and cancer. Further we ask how we can use other environmental factors such as physical exercise and diet to tune microbiota metabolic output to modulate systemic immunity thereby changing cancer outcome.
Dr. Mellors' laboratory focuses on resistance to antiretroviral drugs used for treatment and HIV prevention and on mechanisms of HIV persistence and strategies to deplete the reservoirs that are the barrier to curing HIV infection. His work on HIV reservoirs showed that low-level viremia persists in most individuals on long-term suppressive ART, and that the level of residual viremia is predicted by the level of viremia before ART. Current work focuses on identifying agents to reverse HIV latency and to eliminate HIV infected cells. The impact of innovative therapies on HIV reservoirs is being studied in Phase I/II trials of histone deacetylase inhibitors, monoclonal antibodies to immune checkpoint ligands, monoclonal antibodies to HIV envelope glycoproteins, and TLR agonists.
My research focuses on two areas: (1) Imaging Biomarkers in Cancer: Investigating imaging biomarkers for the early detection, diagnosis, therapy response, and prognosis of cancers, including lung, ovarian, and melanoma; (2) AI in Robotic Surgery: Exploring how AI can improve robotic surgery, such as simulating lung motion during lung biopsy procedures to accurately localize lesions and guide biopsy needle insertion, enhancing precision and reducing complications.
The multidisciplinary environment at Hillman Cancer Center is ideal for integrating my AI methodologies with clinical practices. Access to clinical data and patient cohorts helps validate and refine my AI models, while the collaborative atmosphere fosters innovation, driving clinical applications that benefit cancer patients.
I am a Tenured Professor of Medicine at the University of Pittsburgh, the director of Pitt's CHAllenges in Management and Prevention of Pain (CHAMPP) center, and the PI of a NIDA-funded research center, Tailored Retention and Engagement for Equitable Treatment of OUD and Pain (TREETOP), the goal of which is to improve treatment for comorbid opioid use disorder (OUD) and chronic pain. I am a PhD-trained behavioral scientist and an addiction medicine and palliative care physician who treats individuals with opioid misuse/OUD and chronic pain, including chronic cancer-related chronic pain. I have expertise in medical cannabis and have published 5 peer-reviewed paper related to cannabis policy and the use of cannabis among patients with cancer. I and my team recently published a paper in JAMA Oncology on developing consensus among palliative care and addiction specialists on the appropriateness of various opioid management strategies in individuals with advanced cancer-related pain and opioid misuse or OUD. I have also received an NIH-funded K24 grant, entitled "Mentoring the next generation of researchers at the intersection of opioid use disorder and chronic pain," which will not only assist in the mentorship of a new cadre of professionals, but proposes a new research project that leverages existing Delphi-based preliminary data to develop an implementation strategy bundle to promote the adoption and equitable application of evidence-based approaches for managing opioid misuse/OUD and metastatic cancer-related pain.
Brain Tumor Metabolism and Functional Cancer Genomics Laboratory
Laboratory of brain tumor metabolism and functional cancer genomics laboratory are established and directed by Dr. Antony MichealRaj in September 2021 at the Department of Neurological Surgery, University of Pittsburgh School of Medicine.
We are focused on exploring the underlying disease mechanism of pediatric brain tumors, with a specific interest in pediatric cancer stem cells- brain tumor metabolism and epigenetics and post transcriptional and translational regulation. Our team is investigating following major themes in pediatric ependymomas and gliomas:
1) Functional cancer genomics using in vivo and In vitro CRISPR screens
2) Metabolic dependencies and epigenetic regulation in primary and recurrent tumors
3) Unraveling the crosstalk between cell signaling and epigenetics
4) mRNA regulation and translational control
Since September 2021, the Brain Tumor Metabolism and Functional Cancer Genomics Laboratory explored the molecular network and metabolic dependencies which are essential for pediatric supratentorial ependymomas survival and proliferation. Supratentorial ependymomas (ST-EPNs) are aggressive pediatric forebrain malignancies, which account for 40% of all intracranial ependymomas. Recurrent fusion of ZFTA (previously known as C11orf95) with RELA or other genes such us YAP1, MAML2, MAML3, NCOA2 are identified to be oncogenic drivers of Supratentorial ependymoma which does not have an effective therapeutic option. Up to 40% of children with this Ependymoma succumb to their disease, and survivors are often left disabled because of toxicity from the tumor and treatment. We have made reasonable progress on identifying the abnormal gene elements that could potentially drive this lethal tumor. However, we are still far behind in understanding the molecular network which makes children vulnerable to this tumor. Unraveling this network is very important for novel therapeutic interventions. We have developed disease models from supratentorial ependymoma patients and applied cutting- edge scientific tools to target one gene at a time on a genome-wide scale. In parallel, we have profiled the surgical biopsies abnormal gene expression and protein levels. Through these analyses, we have identified genes that are not mutated but are very important for tumor development. This essential genetic network unraveled the potential cell of origin and suggest the putative oncogenic route of this neoplasm. Additionally, our metabolic profiling and tracing studies in disease models identified the nutrient demand that are required for epigenetics, macromolecular synthesis and bioenergetic processes in supratentorial ependymomas. We are now exploring single and combined therapeutic approaches to target this tumor by blocking the metabolic activity by selective and blood brain penetrant small molecules and nutrient limited- diet. For the first time, we established a transgenic mouse model for supratentorial ependymoma which will be used as primary tool for investigating disease mechanism and novel therapeutic discoveries/validations.
Our team using patient-derived disease models (Cell lines, Xenografts) and transgenic mouse models and cutting edge next-generation genomic technologies (Bulk and single cell sequencing, ChIP seq, long read sequencing), metabolomics (total and targeted), genetic engineering tools (Genome-wide and focused CRISPR screen) to advance our existing knowledge on pediatric brain tumors and probe novel therapeutic options.
Dr. Modugno is a molecular epidemiologist focused on women’s cancers, especially ovarian, breast, and endometrial cancers. Dr. Modugno’s research has examined the underlying epidemiology of ovarian and breast cancer etiology and outcomes with a focus on genetic, hormonal, and immunologic factors. As the Principal Investigator of the HOPE study, one of the largest studies of ovarian cancer risk and prognosis ever conducted in the US (2003-2008), Dr. Modugno was a founding member of the Ovarian Cancer Association Consortium (OCAC), a multinational consortium of ovarian cancer investigators that pools data and resources to investigate ovarian cancer risk and prognostic factors. She currently serves as the OCAC Data Access Chair and is a member of the Steering Committee. She holds similar roles in the international Ovarian Tumor Tissue Association (OTTA), which is investigating the molecular basis for ovarian cancer outcomes. Her recent funding is examining the relationship among humoral and cellular immunity, the gut microbiome, circulating metabolome, and the tumor immune microenvironment in ovarian cancer therapy response.
Dr. Modugno directs the Women's Cancer Biome Program, which is focused on identifying the relationship between the microbiome and cancer/cancer prevention in women. She also oversees the Gynecologic Oncology Biospecimen and Data Bank (ProMark). The repository collects fresh tissue and biospecimens on women with suspected gynecologic malignancies as well as on healthy women per investigator protocols. The repository also banks specimens for retrospective studies. Resources of the repository are available to researchers interested in gynecologic oncology or related research.
Dr. Modugno co-led the Pittsburgh site for the RPCI/HCC Ovarian Cancer SPORE and directed the Pathology and Biospecimen Core and the Developmental and Career Enhancement Programs. The resources and infrastructure developed by Dr. Modugno during her tenure as a RPCI/HCC SPORE co-leader were leveraged to support the subsequent independent HCC Ovarian SPORE submission.
DNA replication remains one of the main targets of cancer therapies as cancer cell generally proliferate faster and are prone to replication stress. My research interests involve studying the control of the initiation of DNA replication under normal conditions, in cancer, and in response to DNA damage. During my postdoctoral work, I have identified the signaling mechanism that mediates rapid and massive dormant origin firing in response to ATR or WEE1 inhibition. As a PI, I use ATR inhibition-induced origin firing, auxin-inducible degron systems, split Turbo-ID proteomics and other innovative cell biology approaches to study the molecular mechanism of the initiation of DNA replication in human cells. Our recent findings include discovery of the non-catalytic function of DNA polymerase epsilon and its dispensability for the assembly of CMG helicase in human cancer cells. My current projects focus on further studies into the non-catalytic function of DNA polymerase epsilon in cancer and non-cancer cells, identification of novel replication initiation factors in human cell lines, and the perturbations in replication proteins in cancers. Knowing the molecular mechanisms of origin firing will lead to developing drugs that specifically manipulate this process making cancer cells susceptible to DNA damage and other therapies.
Dr. Monga is the UPMC Endowed Chair for Experimental Pathology at the University of Pittsburgh, School of Medicine. He is a Professor of Pathology and Medicine and the Associate Dean of Research for the School. He is the Executive Vice Chair of Pathology and the Chief of the Division of Experimental and Translational Pathology. He is the inaugural Director of the Pittsburgh Liver Institute and also the founding Director of P30 funded Pittsburgh Liver Research Center (PLRC), which is 1 of the 17 NIDDK-funded Digestive Disease Research Core Centers and only 1 of the 3 with exclusive liver focus. He also runs a T32 funded training program in Regenerative Medicine. He is an academic physician and has focused on elucidating the cellular and molecular underpinnings of liver injury, repair, and liver cancer for more than 22 years and has been consistently funded by NIH and sponsored research agreements from industry throughout his career. He has published 208 articles, received numerous research and mentoring awards and served on boards of both industry and academia. He has made seminal contributions in this area especially in the understanding of the role of complex signaling pathways such as the Wnt, Hippo and others and several of his findings are now on the verge of being translated into patients.
There are two major research themes within his laboratory. The first focus is in the broad area of liver physiology. This includes the areas of hepatic development, liver regeneration (following surgical resection, drug-induced injury or cholestasis) and metabolic zonation (division of labor within liver lobule). His work has elucidated the cell-molecule circuitry of liver regeneration following hepatectomy showing Wnt2 and Wnt9b release from endothelial cells to activate -catenin in hepatocytes to induce proliferation and regain of hepatic mass. His work also showed an important role of -catenin in hepatoblast proliferation during development and then in hepatocyte maturation. In adult liver, his group has shown that Wnt2-Wnt9b from endothelial cells also control gene expression in hepatocytes located in pericentral region of the liver lobule and hence plays an important role in metabolic zonation. He showed an important redundancy between β-catenin and β-catenin at adherens junction where loss of any one of the two catenins was compensated by the other, whereas dual loss in hepatic epithelial or ‘hepithelial’ cells, led to disruption of blood bile barrier and excessive morbidity. The second major focus in the lab has been on understanding the role of β-catenin gene mutations in liver tumors especially hepatoblastoma and hepatocellular cancer. Since mutations in CTNNB1 are observed in 26-38% of all HCC patients, he has generated very relevant mouse models that represent subset of human HCC using sleeping beauty transposon/transposase and crispr/cas9. These models have lent themselves well to help understand the cooperation of mutant CTNNB1 with other oncogenes such as MET, NFE2L2, YAP and others. Their studies have revealed β-catenin to be a driver mutation whose therapeutic targeting may have a profound impact on the field. They have identified addiction of -catenin gene mutated HCCs to mTORC1 due to excess glutamine production by these tumors, as well as resistance to immune checkpoint inhibitors due to unique biology that leads to dearth of immune cell infiltration within the tumor microenvironment. Several discoveries from his lab are now ready to be translated into the clinic and may have both diagnostic and therapeutic implications.
Dr. Moore focuses his research on the link between viruses and cancer. Through his research, he hopes to answer why some viruses evolve to cause cancer while others cause nothing worse than the common cold. Dr. Moore and his wife, Yuan Chang, MD, discovered Kaposi’s sarcoma-associated herpesvirus (KSHV), also called human herpesvirus 8. KSHV causes Kaposi’s sarcoma, the most common malignancy occurring in AIDS patients. Kaposi’s sarcoma, a disease in which cancer cells are found in the tissues under the skin or mucous membranes, can be very aggressive in people whose immune systems are suppressed. Prior to this discovery, scientists had worked for 20 years to find an infectious agent associated with Kaposi’s sarcoma. He and Dr. Chang also are the discoverers of Merkel cell polyomavirus, which is the culprit that causes the rare and deadly skin cancer, Merkel cell carcinoma.
I am a physician scientist specializing in radiation therapy for the treatment of head and neck cancer and cutaneous malignancies. My laboratory utilizes genetically engineered mouse models, orthotopic syngeneic transplant mouse models, and patient samples to study the development and progression of head and neck squamous cell carcinoma (HNSCC), as well as to evaluate biomarkers and new therapeutic combinations for head and neck cancer. We are particularly interested in molecular characteristics of radiation resistance and immune dysregulation within the tumor microenvironment of HNSCC.
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.
As a faculty in the Department of Radiation Oncology, I have been working on multiple cancer-related projects, including: 1. Using radiation as a modality in ovarian cancer mouse models in the presence of mitigators of radiation damage; 2. Ameliorating fibrosis in post-irradiated surviving lung cancer patients; 3. Evaluating senescence as an important factor in lung cancer progression.
DNA double-strand breaks (DSBs) are the most deleterious of DNA lesions and must be timely and accurately repaired to prevent genome instability. Telomeres, the ends of our linear chromosomes, resemble DSBs and must be protected from improper DNA damage signaling and repair. Telomeres also shorten with every cell division, which provides a tumor suppressor function, but critically short telomeres activate senescence and aging phenotypes. How DSBs are recognized and repaired but telomeres are protected from an improper DNA damage response is a major question in both cancer and aging biology. My laboratory combines cell biology, biochemistry, and single-molecule microscopy to answer these fundamental questions in order to understand the growth of cancer cells and develop new therapeutic avenues for targeting tumors.
