March 2022
New Myelofibrosis Treatment
A new drug for the treatment of cytopenic myelofibrosis— VONJO™ (pacritonib)—was approved in February by the Food and Drug Administration (FDA), thanks to results from a pivotal clinical trial led by John Mascarenhas, MD. VONJO is the first approved therapy specifically for patients who have myelofibrosis with severe thrombocytopenia.
The FDA’s decision to approve VONJO, a novel oral kinase inhibitor, is based on data from the phase 3 PERSIST-2 trial, reported by Dr. Mascarenhas and colleagues in JAMA Oncology, 2018 May (Pacritinib vs Best Available Therapy, Including Ruxolitinib, in Patients With Myelofibrosis: A Randomized Clinical Trial). Findings from the trial showed that pacritinib, an oral JAK2/FLT3 inhibitor, was significantly more effective than the best available therapy, including ruxolitinib, for reducing splenomegaly and symptoms in patients with myelofibrosis and thrombocytopenia.

“Myelofibrosis with severe thrombocytopenia, defined as blood platelet counts below 50 × 109/L, has been shown to result in poor survival outcomes coupled with debilitating symptoms. Limited treatment options have rendered this disease as an area of urgent unmet medical need. I am pleased to see that a new, effective and safe treatment option is now available for these patients,” said Dr. Mascarenhas.
Faculty News
Sacha Gnjatic, PhD, has been promoted to Professor of Oncological Sciences, along with secondary promotions to Professor in the Departments of Medicine (Hematology and Medical Oncology) and Pathology (Molecular and Cell-Based Medicine). Dr. Gnjatic’s lab develops and analyzes immune correlates of cancer immunotherapies, from patient blood and tissues, to define biomarkers of response or adverse events, and to understand immunological mechanisms at play in clinical trials.
Sacha Gnjatic, PhD, Jean-Frederic Colombel, MD, and Jeremiah Faith, PhD, are conducting a research study investigating immune-related colitis following checkpoint inhibitor therapy in patients with cancer. Eligible patients must be scheduled to receive a treatment regimen for solid tumors that includes CTLA-4 blockade (ipilimumab or tremelimumab), alone or in combination with other drugs. Study participation involves collection of biospecimens, which will be analyzed at Mount Sinai’s Human Immune Monitoring Center. To learn more or refer patients, contact Diane DelValle at [email protected] or 212-824-9624.
Dan Hasson, PhD, has been promoted to Associate Professor of Oncological Sciences. A member of the Bernstein Laboratory and Co-director of the TCI Bioinformatics for Next Generation Sequencing (BINGS) core, Dr. Hasson utilizes genomic approaches and computational tools to support studies on the role of epigenetics in cancer.
Awards and Honors
Fred Hirsh, MD, PhD, received the 2022 Heine H. Hansen Award from the European Society for Medical Oncology in recognition of his lifelong outstanding contribution to lung cancer research. Dr. Hirsh will deliver his award lecture on March 30 at the 2022 European Lung Cancer Conference.

Xiaoyu Song, DrPH, Assistant Professor of Population Health Science and Policy, is the recipient of the Distinguished Scholars Award from the Icahn School of Medicine at Mount Sinai. The award recognizes early career investigators with independent research programs who are integrating family caretaking responsibilities into their careers. Dr. Song’s studies have helped accelerate the understanding of the molecular basis of cancer through the application of large-scale proteogenomics data analysis. She has been mentored by Pei Wang, PhD, Professor of Genetics and Genomic Sciences, and Madhu Mazumdar, PhD, Director of TCI’s Biostatistics Shared Resource Facility.
Grant Awards
Yelena Ginzburg, MD, has received renewal of her R01 grant—The Role of Erythroferrone in Regulating Bone Matabolism in Beta-Thalassemia—from the National Institute of Diabetes and Digestive and Kidney Diseases. In this renewal, Dr. Ginzburg will be exploring the cellular mechanism of action of erythroferrone (ERFE) and its role in disordered bone metabolism. The goal is to provide novel insights into the complex interplay between regulation of iron metabolism and bone homeostasis in diseases of dysregulated erythropoiesis and support the rationale to further investigate the therapeutic potential of ERFE for β-thalassemia.
Miriam Merad, MD, PhD, has received renewal of her R01 grant—Defining Pathogenic Mechanisms and Therapeutic Opportunities for Langerhans Cell Histiocytosis—from the National Cancer Institute. In this renewal, Dr. Merad will define the roles of cell of origin, differentiation of cells harboring activating MAPK pathway mutations, and the impact of target tissue on pathogenesis in order to identify and test novel therapeutic strategies to improve outcomes of patients with Langerhans cell histiocytosis.
Marta Luksza, PhD, computer scientist working on topics at the interface of evolutionary biology and immunology in the Departments of Oncological Sciences and Genetics and Genomic Sciences, has been awarded an R01 grant—Predictive Fitness Models for Influenza Vaccine Strain Selection—from the National Institute of Allergy and Infectious Diseases. Dr. Luksza will develop a predictive fitness model that accurately accounts for immune recognition of influenza antigens and for the epidemiological factors that create the environment for the evolution of the virus, in order to quantify fitness effects that are imposed on the virus. Using machine learning approaches, Dr. Luksza will leverage large sequence and phenotypic datasets to propose objective criteria for the influenza vaccine strain selection.
Alessandro Lagana, PhD, has received an American Society of Hematology Bridge Grant to support his research on identifying and validating novel molecular drivers of multiple myeloma (MM) subtypes through a combination of computational analyses and laboratory experiments. Building on their recent multi-omics classification of MM, Dr. Lagana and team will use clinical and next-generation sequencing data to learn the structure of a causal Bayesian network model which will be interrogated to identify the key drivers of MM subtypes. They will validate promising candidate drivers for each group in vitro by targeted CRISPR-mediated knockdown screen and lentiviral vector-mediated gene overexpression on human MM cell lines and primary cells.
Marina Bárcena Varela, PhD, post-doctoral fellow in the Lujambio Laboratory, has received a 2022 Cholangiocarcinoma Foundation Research Fellowship for her project, Harnessing the Microbiome for Precision Chlangiocarcinoma (CCA) Immunotherapy. Using precision animal models of CCA, Dr. Bárcena will aim to identify bacterial populations from the gut that affect the response to current available immunotherapies and design microbiome-based tools to improve response rates.
The Tisch Cancer Institute Scholars Program provides early- and mid-career investigators with annual awards to support innovative cancer research. Of the 74 applications reviewed for funding in 2022, three were selected:

  • Joshua Brody, MD—Preventing antigen escape relapse post-immunotherapy by potentiating fas-mediated bystander signaling
  • Nihal Mohamed, PhD—Mobile Ostomates REsources intervention for patients and caregivers (MORE)
  • David Mulholland, PhD—Therapeutic modulation of intermediate tumor subpopulations to delay treatment induced neuroendocrine prostate cancer

Shared Resources:
Flow Cytometry Equipment Status Update
To ensure best utilization of flow cytometry equipment and minimize disruption to experiments when machines are undergoing repair, the Flow Cytometry Shared Resource Facility (FCSRF) has put in place mechanisms for real-time information on the status of machines and alternative options.

The status of machines can be checked via a continually updated spreadsheet. Additionally, announcements are posted regularly on Twitter: @ISMMSFlow

When necessary, FCSRF is transferring reservations to other available machines at Mount Sinai and coordinating backup usage with individual labs and other departments that have cytometers.

Importantly, researchers are encouraged to contact FCSRF staff if there is an issue with a machine to facilitate a quick response.

           Jordi Ochando, PhD, Director
           [email protected]

           Christopher Bare, Laboratory Operations Manager
           [email protected]

For further information, visit the FSCSF site or contact Jerry Chipuk, PhD, Associate Director of Basic Science Shared Resources at TCI.
Brian Brown, PhD, and colleagues

Cell. 2022 Mar 14
Brian Brown’s lab and colleagues report on an approach they developed for functional genomics—Perturb-map—that enables pooled CRISPR screens to be resolved within the tissue by multiplex imaging and spatial transcriptomics. They applied Perturb-map to knock out dozens of genes in parallel in a mouse model of lung cancer and simultaneously assessed how each knockout influenced tumor growth, histopathology, and immune composition. They also paired Perturb-map and spatial transcriptomics for unbiased analysis of CRISPR-edited tumors. Amongst the findings, the study revealed that loss of the TGFβ receptor on lung cancer cells promotes remodeling of the lung tumor microenvironment and T cell exclusion which was concomitant with a signature indicative of TGFβ-mediated fibroblast activation in the tumors. 
Cell Reports Methods. 2022 Mar 9
Developmental, homeostatic, and pharmacological pro-apoptotic signals converge by activating the BCL-2 family member, BAX. Studies investigating molecular regulation of BAX are commonly limited to methodologies measuring endpoint phenotypes and do not assess activation of monomeric BAX. Dr. Chipuk and colleagues present FLAMBE, a fluorescence polarization ligand assay for monitoring BAX early-activation, which measures activation-induced release of a peptide probe in real-time. Using complementary parallel and tandem biochemical techniques, they validate, corroborate, and apply FLAMBE to a contemporary repertoire of BAX modulators, characterizing their contributions within the early steps of BAX activation. Additionally, they use FLAMBE to reveal that historically “dead” BAX mutants remain responsive to activation as quasi-functional monomers. They also identify data metrics for comparative analyses and demonstrate that FLAMBE data align with downstream functional observations. Collectively, FLAMBE advances our conceptualization of BAX activation and fills a methodological void for studying BAX with broad applications in cell biology and therapeutic development.
Miriam Merad, MD, PhD, and colleagues

Nature Cancer. 2022 Mar 3. PMID: 35241835
This study characterizes the interactions between a key subset of T cells (named T-helper tumor (ThT) cells) and antigen-presenting dendritic cells in the tumor microenvironment. Using a unique assay developed by author Merav Cohen PhD (with the Weizmann Institute of Science), the researchers were able to analyze cells that are physically interacting in human tumors and gain insights about their molecular programs. This provides a path for blocking some of the molecules that are induced during the interactions that limit antitumor activity of T cells. Findings support the modulation of ThT-dendritic cell interaction checkpoints as a major interventional strategy in immunotherapy.
Urologic Oncology. 2022 Mar. PMID: 35140050
This study compared patterns of recurrence, recurrence-free survival, cancer-specific survival, and overall survival between patients who underwent open or minimally-invasive partial nephrectomy and had malignant pathology. Findings indicated that surgical approach was not predictive of location of recurrence, time to recurrence, or time from recurrence to death. The researchers concluded that higher level evidence is required to further delineate the relationship of surgical approach for nephron sparing surgery to oncological outcomes.

Nature Communications. 2022 Feb 4. PMID: 35121738
This study investigated the gain-of-function mechanism through which certain p53 missense mutants induce the transformed phenotype and identifies a paradigm for cancer driver mutations that act indirectly to hyperactivate wild-type RhoA mechano-signaling to levels required for oncogenic TEAD/YAP transcription. It also investigated the role of physiological RhoA/ROCK mechano-signaling in upregulating TEAD/YAP transcription and the proliferation of tumors with Hippo pathway genetic aberrations. Findings demonstrate that ROCK inhibitors antagonize tumor growth by either mechanism and support continued efforts to exploit the potential of ROCK inhibitors for selective targeting of these human malignancies.

Nature Communications. 2022 Feb 25. PMID: 35217661
DNA polymerase zeta plays an important role in the replication of damaged or mismatched DNA and in the prevention of cancer. Drs. Malik and Aggarwal report on a cryo-EM structure of DNA polymerase zeta with mismatched DNA, which provides new insights into mechanisms that either stall or favor continued DNA synthesis in eukaryotic cells.

Journal for Immunotherapy of Cancer. 2022 Feb. PMID: 35190376
This study investigated the mechanisms of CD4 + T cell-mediated tumor protection in a mouse model of multiple myeloma in order to optimize therapeutic vaccine strategies. Findings indicate that activation of CD8 cytolytic T lymphocyte (CTL) activity against antigens not present in the vaccine is a major mechanisms of tumor immunity and highlight the impact of tumor vaccine formulation on the efficacy of the vaccine to induce elimination of tumor cells.
Upcoming Presentations
TCI Seminar Series
Tuesdays at 12 noon

March 22
Head, Cancer Genetics Laboratory
McGill Centre for Translational Research in Cancer
Topic: The Genetics of Non-Epithelial Ovarian Cancer One Family at a Time

April 5
Director, Cancer Data Science, Jonsson Comprehensive Cancer Center
Topic: The Origins of Cancer Aggression

Hematology/Medical Oncology Grand Rounds
Thursdays at 8:30 am
March 24
Director, Head and Neck Cancer Oncology Disease Group
Johns Hopkins Medicine
Topic: Head and Neck Cancer Update
March 31
Head of the Study Center, Department of Haematology/Oncology and the University Cancer Center, University Hospital in Frankfurt
Principal Investigator of the German Consortium for Translational Cancer Research and the Frankfurt Cancer Institute
Topic: TBA
April 21
Leslye M. Heisler Associate Professor for Lung Cancer Excellence
Penn Medicine
Topic: TBA
April 28
Jodi Fisher Horowitz Professor in Leukemia Care Excellence
Director, Cell Therapy and Transplantation
Penn Medicine
Topic: TBA

TCI Translational Oncology Seminar Series
Thursday, April 14, 8:30 am
Director, Mark Lebwohl Center for Neuroinflammation and Sensation
Department of Dermatology
Vice Chair of Research, Icahn School of Medicine at Mount Sinai
Topic: TBA
Cesar Rodriguez, MD, will provide an overview of multiple myeloma and updates on the latest advances
in research and treatment.
March 29
Leukemia and Lymphoma Society Patient Education

Do you have news for the next issue of TCI Connections

Please send to Janet Aronson (646-745-6376).

Remember to share breaking news and high impact news that might be appropriate for media coverage with Marlene Naanes (929-237-5802) in the Press Office. This may include pending FDA drug/device approvals, studies/trial results being published in high-impact journals, and patient stories. The more lead time you can give Marlene, the better—ideally, four weeks or when a paper is accepted by the journal. Embargoes will always be honored and news will only be released with your approval.
  TCI Connections  is a monthly publication of The Tisch Cancer Institute
Ramon Parsons, MD, PhD, Director
Janet Aronson , Editor
Past issues of  TCI Connections  are available on the TCI website