The Tisch Cancer Institute

In the News

Aimee Lucas, MD

Familial Pancreatic Ductal Adenocarcinoma

Am J Pathol. 2019 Jan;189(1), PMID: PMID: 30558720

Pancreatic ductal adenocarcinoma (PDAC), although a rare disease, has a poor prognosis.

Focused screening of individuals that are at high risk of developing PDAC because of modifiable and nonmodifiable risk factors may improve timing of detection, disease morbidity, and mortality. A better understanding of the pathologic mechanisms of inflammation, cell proliferation, and decreased apoptosis that lead to PDAC in high-risk individuals may help guide the development of screening methods and thus improve outcomes.

Samuel Sidi, PhD

An IRAK1-PIN1 signalling axis drives intrinsic tumour resistance to radiation therapy

Nature Cell Biology. 2019 Feb;21(2):203-213. PMID: 30664786

More than 60 percent of cancer patients receive radiation therapy (RT) as part of their treatment, yet the mechanisms by which tumors evade RT remain poorly understood. Through an unbiased chemical-genetic screen in a zebrafish, we identified a novel role for the innate immune kinase IRAK1 as a driver of tumor resistance to RT, a role confirmed in multiple pre-clinical models and further supported by gene-expression data from patients with head and neck cancer. The data identify IRAK1 inhibition as a targeted therapy for radioresistant cancer.   

 Zeynep H. Gümüş, PhD

 Rare, Pathogenic Germline Variants in Fanconi Anemia Genes Increase Risk for Squamous Lung Cancer

Clin Cancer Res. 2019 Mar 1, PMID: 30425093

The authors identified rare, pathogenic germline variants in Fanconi Anemia (FA) genes as risk factors for increased risk of squamous lung cancer (SqCC). Their findings increase understanding of SqCC predisposition and can be used toward development of a genetic diagnostic test to identify high-risk individuals who can benefit from personalized intensive surveillance, early detection and prevention strategies.

 Ashutosh Tewari, MD

A Transcriptomic Signature of Tertiary Gleason 5 Predicts Worse Clinicopathological Outcome

BJU Int. 2019 Mar 2. PMID: 30825357

This study is the first that correlates TP5 with higher metastatic tumor potential, evaluated by means of the Decipher (R) score. This corroborates clinical observations for which patients with Gleason 7 with TP5 harbor poorer prognosis with respect to their counterpart without TP5. This study represents the first that investigates the gene expression profiling of specimens with TP5, as a proxy of early tumor de-differentiation. The researchers were able to elucidate unique genomic features in case of presence of TP5. The information has potential clinical applications during patient counseling regarding an individual’s risk of harboring a worse cancer phenotype and/or developing metastasis during post-operative follow-up.

Augusto Villanueva, MD, PhD

Hepatocellular Carcinoma

New England Journal of Medicine. 2019 Apr. 11. PMID: 30970190

This review summarizes the main genetic alterations in hepatocellular carcinoma, key epidemiologic features, and evidence-based approaches to management.

Josep Llovet, MD, et al.

Randomized trials and endpoints in advanced HCC: Role of PFS as a surrogate of survival

Journal of Hepatology. 2019 Mar. 12. PMID: 30943423

In this review, the authors discuss the reasons for positive or negative phase III trials in advanced hepatocellular carcinoma (HCC), and the strengths and limitations of surrogate endpoints (progression-free survival (PFS), time to progression, and objective response rate) to predict survival. They propose a conservative threshold of PFS (HR< 0.6) as a surrogate primary end-point of survival in advanced HCC trials.

Brett Miles, DDS, MD, Eric Genden, MD, et al.

Initial presentation of human papillomavirus-related head and neck cancer: A retrospective review.

Laryngoscope. 2019 Apr. PMID: 30194702

In this study the authors outline the common presenting signs of human papillomavirus-positive oropharyngeal squamous cell carcinoma, providing physicians with a better understanding of initial cancer presentation and leading to earlier diagnosis and improved outcomes.

Hearn Jay Cho, MD, PhD, Sacha Gnjatic, PhD, et al.

Autologous Lymphocyte Infusion Supports Tumor Antigen Vaccine-Induced Immunity in Autologous Stem Cell Transplant for Multiple Myeloma

Cancer Immunology Research. 2019 Apr. PMID: 30745365

Reported results provide proof-of-principle that autologous lymphocyte infusion augmentation of autologous stem cell transplant (autoSCT) is a promising component for multiple myeloma combination immunotherapy. The combined vaccine and autologous lymphocyte infusion augmentation strategy was effective in stimulating humoral and Th1-biased CD4+ T-cell responses to the immunized antigen, despite the immune compromise exhibited by myeloma patients in general and especially after autoSCT, indicating the power of this strategy to generate antigen-specific immunity in the autoSCT setting.

Helene Salmon, PhD , Sacha Gnjatic, PhD, Miriam Merad, MD, PhD, et al.

Host tissue determinants of tumour immunity

Nature Reviews, Cancer. 2019 Apr. PMID: 30867580

In this review, the authors discuss how tissue-specific determinants might influence tumor development and how unravelling the tissue-specific contribution to tumor immunity should: 1) support development of precise immunotherapeutic strategies for patients with cancer, and 2) help inform the mechanisms of resistance to treatment and transform the design of combination therapy trials.

Jerry Chipuk, PhD, et al.

Mitochondrial origins of fractional control in regulated cell death

Nature Communications. 2019 Mar. PMID: 30899020

The researchers use the response to TNF-related apoptosis inducing ligand (TRAIL) and a new statistical framework for DEtermining Parameter Influence on Cell-to-cell variability Through the Influence of Varience Explained (DEPICTIVE) to demonstrate that variable mitochondria abundance correlates with cell survival and determines the fractional cell death response.

The study suggests that inhibitors of anti-apoptotic Bcl-2 family proteins, used in cancer treatment, may increase the diversity of cellular responses, enhancing resistance to treatment.

Joshua Brody, MD, Miriam Merad, MD, PhD, et al.

Systemic clinical tumor regressions and potentiation of PD1 blockade with in situ vaccination

Nature Medicine. 2019 Apr. 8.

Indolent non-Hodgkin’s lymphomas (iNHLs) are incurable with standard therapy and poorly responsive to checkpoint blockade. Although lymphoma cells are efficiently killed by primed T cells, in vivo priming of anti-lymphoma T cells has been elusive. The data demonstrate that increasing and activating intratumoral, cross-presenting dendritic cells at the tumor site is achievable and can prime tumor-specific T cells, restore efficacy of checkpoint blockade, and yield superior antitumor immunity. 

Doris Germain, PhD, et al.

Parity predisposes breasts to the oncogenic action of PAPP-A and activation of the collagen receptor DDR2.

Breast Cancer Research 2019 May 2. PMID: 31046834

Study data indicate that history of pregnancy and lactation, combined with the expression of pregnancy-associated plasma protein A (PAPP-A)-driven genetic signature, holds the potential to identify patients at higher risk of metastatic disease and develop targeted intervention.

Jerry Chipuk, PhD, et al.

MDM2 Integrates Cellular Respiration and Apoptotic Signaling through NDUFS1 and the Mitochondrial Network

Molecular Cell. 2019 May 2. PMID: 30879903

Results of this study show that MDM2, a gene commonly amplified in cancer, alters cellular metabolism influencing energy production, stress signaling, and cell survival pathways. This newly discovered biological mechanism will impact future patient care by providing a clearer understanding of the role of MDM2 amplification in disease. Additionally, MDM2’s regulation of mitochondrial biology engages an understanding of cell metabolism, which promises to be useful in cancer diagnosis and treatment, and influence drug discovery and development of new therapeutic options. 

Manjeet Chadha, MD, Elisa Port, MD, et al.

The Evolving and Multidisciplinary Considerations in Nodal Radiation in Breast Cancer

Seminars in Radiation Oncology. 2019 Apr. PMID: 30827453

This paper describes the role of regional nodal irradiation in the context of the de-escalation of axillary surgery, improved understanding of the molecular and pathologic features of breast cancer, and increasing use of neoadjuvant chemotherapy. It also summarizes key clinical trials aimed at optimizing the management of regional lymph nodes in concert with the ultimate goal of assessing each patient’s risk for recurrence and individualizing multidisciplinary management for improved clinical outcomes.

John Mascarenhas, MD, et al.

Relevant updates in systemic mastocytosis

Leukemia Research. 2019 Apr 4. PMID: 30978435

Systemic mastocytosis (SM) is a rare myeloproliferative neoplasm characterized by a clonal proliferation of mast cells and their subsequent infiltration of either the bone marrow or extracutaneous, extramedullary sites. Increased recognition of SM and increased understanding of its biology have led to the translation of mechanism-based targeted therapies. For example, the recent approval of the KIT inhibitor, midostuarin, has spurred development other kinase inhibitors targeting signaling pathways. This article describes the pathogenesis, epidemiology and diagnosis of SM and provides an update on current treatment and future therapies in development

Juan Wisnivesky, MD, DrPH, Charles Powell, MD, Emanuela Taioli, MD, PhD, et al.

Outcomes of Older Patients with Pulmonary Fibrosis and Non-Small Cell Lung Cancer

Annals of the American Thoracic Society. 2019 Apr 16. PMID: 30990757

This study, based on review of 54,453 non-small cell lung cancer patients (NSCLC), found that patients with idiopathic pulmonary fibrosis (IPF) and NSCLC have a greater proportion of early stage disease of squamous histology in a lower lobe distribution—a factor that may need to be incorporated into risk models for lung nodule management in IPF patients—and that IPF is an independent factor for increased NSCLC and overall mortality.  The study reinforces the need for further research to identify the best strategies to control and treat NSCLC in patients with IPF.

Roland Friedel, PhD, et al.

Gene signatures of quiescent glioblastoma cells reveal mesenchymal shift and interactions with niche microenvironment

EBioMedicine. 2019 Apr 2. PMID: 30952620

The researchers isolated quiescent glioblastoma (qGBM) cells—a potential source of GBM tumor recurrence—to examine stem cell properties and therapy resistance from a 3D GBM organoid model. Findings support the presence of a quiescent cell population that displays self-renewal capacity, high therapy resistance, and mesenchymal gene signatures, and reveal how GBM cells may acquire and maintain quiescence through extracellular matrix organization and interaction with niche factors such as transforming growth factor beta (TGFβ) and hypoxia. These findings can inform strategies for targeting the quiescent population of GBM.

Amaia Lujambio, PhD, et al.

Functional screening to identify senescence regulators in cancer

Current Opinion in Genetics & Development. 2019 Mar 13. PMID: 30877988

Cellular senescence—irreversible cell cycle arrest—can occur in response to several triggers, in different cell types and tissues, including cancer cells, and entails a number of phenotypes and effector mechanisms. This review focuses on work performed over the last few years, emerging technologies, and future perspectives in the field of functional screening to study senescence in cancer and harness it to our advantage.

Nikhil Waingankar, MD, MSHP; Rachel Jia, PhD, Matthew Galsky, MD, et al.

The impact of pathologic response to neoadjuvant chemotherapy on conditional survival among patients with muscle-invasive bladder cancer

Urologic Oncology. 2019 May 18. PMID: 31109837

This study found that muscle-invasive bladder cancer patients with pathologic complete response after neoadjuvant chemotherapy have improved survival relative to patients with pathologic residual disease (pRD) following radical cystectomy, and that the survival advantage does not significantly change over time. These findings may inform novel adjuvant approaches for patients with pRD.

Doris Germain, PhD, et al.

Mitohormesis primes tumor invasion and metastasis

Cell Reports. 2019 May 21. PMID: 31116976

This study demonstrates that mitohormesis, a phenomenon involving activation of cytoprotective mechanisms and normally associated with health and longevity, is perniciously used by cancer cells to promote tumor progression. Mitohormesis in breast cancer cells results in persistent activation of the mitochondrial unfolded protein response (UPRmt) and reduction in oxidative stress, making the cancer cells more metastatic. Study findings indicate that breast cancer patients with elevated UPRmt experience significantly worse clinical outcomes. 

 Erdem Bangi, PhD, Celina Ang, MD, Marshall Posner, MD, Ross Cagan, PhD, et al.

 A personalized platform identifies trametinib plus zoledronate for a patient with KRAS-mutant metastatic colorectal cancer

Science Advances. 22 May 2019. PMID:

This study presents the results of treating a patient with KRAS-mutant metastatic colon cancer using Drosophila as a personalized cancer drug discovery platform. Following extensive genomic analysis that revealed nine key driver mutations, robotic-based high-throughput screening was used to identify a novel combination—trametinib plus zoledronate—that improved survival of the personalized Drosophila model and subsequently led to a strong partial response in the patient. This Drosophila model is one of the most genetically complex transgenic whole-animal disease models described to date. It can be adapted for use in other tumor types and may prove especially useful in tumors with challenging profiles.

 Julio Aguirre-Ghiso, PhD, et al.

 The importance of developing therapies targeting the biological spectrum of metastatic disease.

Clinical & Experimental Metastasis. 2019 May 17. PMID: 31102066

This commentary highlights the importance of studying all stages of the metastatic process, including early stages before clinical disease evidence that will require strategies to prevent disseminated tumor cells from emerging from dormancy, and late stages characterized by overt disease progression. 

Ajai Chari, MD, et al.

Daratumumab Plus Carfilzomib and Dexamethasone in Patients With Relapsed or RefractoryMultiple Myeloma

Blood. 2019 May 21. PMID: 3113777

This phase 1b study evaluated daratumumab plus carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma after 1-3 prior lines of therapy, including bortezomib and an immunomodulatory drug. The regimen was well tolerated and demonstrated deep, durable responses, even for patients refractory to lenalidomide.

Joshua Brody, MD, et al.

Pathogen molecular pattern receptor agonists: treating cancer by mimicking infection

Clinical Cancer Research. 2019 May 23. PMID: 31123052

The immunostimulatory properties of pattern recognition receptors (PRRs)—a diverse family of receptors that alarm the immune system of an invading microbe—can drive reprogramming of the immune suppressive tumor microenvironment and de-novo tumor-specific T cell responses. This makes PRR-targeting therapies an attractive strategy for treating cancer. This paper addresses PRR mechanisms and clinical implications, providing a detailed overview of the role of PRRs in immuno-oncology.

Amaia Lujambio, PhD, et al. 

β-catenin activation promotes immune escape and resistance to anti-PD-1 therapy in hepatocellular carcinoma  

Cancer Discovery. 2019 Jun 11. PMID: 31186238

Using a novel mouse model of HCC, the researchers show that b- catenin activation promotes immune evasion and resistance to anti-PD-1 therapy, which is relevant to human disease and could provide the rationale for improved patient selection and personalized cancer immunotherapies.

Vaibhav Patel, MD, William Oh, MD

The evolving landscape of immunotherapy in advanced prostate cancer

Immunotherapy. 2019 Jul. PMID: 31161846

The authors describe the early experiences of immune checkpoint blockade and therapeutic vaccines in castration-resistant prostate cancer (CRPC), and outline strategies to overcome immune resistance and emerging immunotherapeutic platforms.

Yixuan Gong, PhD, Li Wang, PhD, Emanuela Taioli, MD, PhD, William Oh, MD, et al.

Prostate Cancer in World Trade Center Responders Demonstrates Evidence of an Inflammatory Cascade

Molecular Cancer Research. 2019 Jun 20. PMID: 31221798

Researchers found that World Trade Center responders with prostate cancer showed signs that inflammation was activated in the prostate after exposure to the toxic dust. Results indicated there was an increase in an inflammatory T-cell called Th 17 in the group exposed to the toxic dust. This exposure may have increased the inflammatory cascade within the prostate, contributing to the risk of developing aggressive prostate cancer.

Xiaoyu Song, DrPH, et al.

Insights into impact of DNA copy number alteration and methylation on the proteogenomic landscape in human ovarian cancer via a multi-omics integrative analysis

Molecular & Cellular Proteomics. 2019 Jun 21. PMID: 31227599

This study reports on a novel integrative analysis tool, iProFun, to screen for Proteogenomic Functional traits perturbed by DNA copy number alterations and methylations. The goal is to characterize functional consequences of DNA copy number and methylation alterations in tumors and facilitate screening for cancer drivers contributing to tumor initiation and progression. The researchers applied iProFun to ovarian high-grade serous carcinoma data from The Cancer Genome Atlas and Clinical Proteomic Tumor Analysis Consortium to identify genes that could serve as potential drug targets.

 Cansu Cimen Bozkus, PhD, Nina Bhardwaj, MD, PhD, Camelia Iancu-Rubin, PhD, et al.

Immune Checkpoint Blockade Enhances Shared Neoantigen-Induced T Cell Immunity Directed against Mutated Calreticulin in Myeloproliferative Neoplasms

Cancer Discovery. 2019 Jul 2. PMID: 31266769

This study reports that mutations in the calreticulin (CALR) gene, which drive transformation in myeloproliferative neoplasms (MPN), elicit T cell responses that can be further enhanced by checkpoint blockade, suggesting immunotherapies could be employed to eliminate CALR+ malignant cells in MPN.
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John Sfakianos, MD, Peter Wiklund, MD, PhD, Matthew Galsky, MD, et al.

The Natural History of Untreated Muscle Invasive Bladder Cancer

BJU International. 2019 Jul16. PMID: 31310696

This study describes the natural history of untreated muscle invasive bladder cancer (MIBC) and compares the oncological outcomes of treated and untreated patients. Findings, which indicate that untreated patients with MIBC are at very high risk for near term cancer specific mortality, may inform integrating curative intent therapy, particularly in older patients.

John Mascarenhas, MD, et al.

Blastic Plasmacytoid Dendritic Cell Neoplasm-Current Insights

Clinical Lymphoma, Myeloma & Leukemia. 2019 Jun 13. PMID: 31281107

In this report, the authors review etiology, summarize diagnostic criteria, and discuss historic treatments and novel therapies for blastic plasmacytoid dendritic cell neoplasm. They note that advances in pathobiological understanding and progress in immunotherapeutic options offer promise for novel therapeutic strategies for patients with this rare malignancy that has universally poor outcomes.

Joshua Brody, MD, et al.

Anti-tumor T-cell homeostatic activation is uncoupled from homeostatic inhibition by checkpoint blockade

Cancer Discovery. 2019 Aug 2. PMID: 31375522

Researchers investigated the unconventional use of dual checkpoint blockade (dCB) during adoptive T cell transfer post-lymphodepletion. Findings indicate that dCB protects transplanted T-cells from inhibitory signaling and potentiates their homeostatic activation. This increased T-cell activation from the combination of transfer and dCB—referred to as “immunotransplant”—significantly amplified anti-tumor immune responses resulting in durable tumor regressions in lymphoma, lung cancer, and melanoma, even when dCB alone yielded no apparent anti-tumor effect. These findings reveal a novel T-cell regulatory mechanism and suggest a therapeutic approach for checkpoint-refractory tumors, now in clinical trial for patients with aggressive non-Hodgkin lymphomas (NCT03305445).

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John Mascarehnhas, MD, Ronald Hoffman, MD, et al.

Oral Idasanutlin in Patients with Polycythemia Vera

Blood. 2019 Jun 5. PMID: 31167802

This article reports on an investigator-initiated phase 1 trial of the oral MDM2 antagonist, idasanutlin, in patients with high-risk polycythemia vera (PV) and essential thrombocytopenia who had failed at least one prior therapy. Results demonstrating a high degree of clinical efficacy indicate that idasanutlin is a promising novel agent for PV and have led to a global phase 2 trial.

Li Wang, PhD, Yixuan Gong, PhD, Matthew Galsky, MD, et al.

Fibroblast Growth Factor Receptor 3 Alterations and Response to PD-1/PD-L1 Blockade in Patients with Metastatic Urothelial Cancer

European Urology. 2019 Jul 1. PMID: 31272788

Findings demonstrate that FGFR3 mutation status in urothelial cancers (UC) is not a biomarker of resistance to checkpoint inhibition (CPI). Single-agent activity of both FGFR3 inhibitors and CPI in FGFR3-mutant UC, and potential non-cross resistance provide a rationale for combination approaches.

 Doris Germain, PhD, et al.

 SOD1 is essential for oncogene-driven mammary tumor formation but dispensable for normal development and proliferation

Oncogene. 2019 Jul. PMID: 3122103

This study investigated the role of the dismutase SOD1 in mammary gland tumorigenesis as well as in normal mammary gland development. Results identify SOD1 as an ideal target for cancer therapy since SOD1 inhibitors hold the potential to prevent the growth of cancer cells of diverse genotypes while sparing normal tissues. SOD1 may be a universal target by affecting a housekeeping function rather than a specific oncogenic driver.

Krzysztof Misiukiewicz, MD, Vishal Gupta, MD, Marshall Posner, MD, et al.

Standard of care vs reduced-dose chemoradiation after induction chemotherapy in HPV+ oropharyngeal carcinoma patients: The Quarterback trial

Oral Oncology. 2091 Aug. PMID: 31345387

This study provides valuable data and support for performing Phase 3 trials utilizing induction chemotherapy to reduce chemoradiotherapy dose, and thereby reduce toxicity, in patients with locally advanced Human Papillomavirus oropharyngeal carcinoma.

Sezen Vatansever, MD, PhD, Zeynep Gumus, PhD

Oncogenic G12D mutation alters local conformations and dynamics of K-Ras

Scientific Reports. 13 Aug 2019.

This detailed description of G12D mutation effects on the local dynamic characteristics of both active and inactive protein helps enhance our understanding of local K-Ras dynamics, and can inform studies on the development of direct inhibitors towards the treatment of K-RasG12D-driven cancers.

Lillian Varricchio, PhD, Anna Migliaccio, PhD, James Bieker, PhD, et al.

Genetic disarray follows mutant KLF1-E325K expression in a congenital dyserythropoieticanemia patient

Haematologica. 2019 Mar 14. PMID: 30872368

Researchers expanded erythroid cells from a CDA type IV patient’s peripheral blood and analyzed its global RNA expression pattern. They found that a large number of erythroid pathways were disrupted, particularly those related to membrane transport, globin regulation, and iron utilization. The altered genetics lead to significant deficits in differentiation.

Concise Summaries of Cancer: 2019 Edition

Mount Sinai Expert Guides: Oncology features latest updates on oncology, hematology, bone marrow transplant, and multidisciplinary care of cancer patients. Full book.  Editors: Ajai Chari, MD; William Oh, MD

Jerry Chipuk, PhD, et al.

Single-Cell and Population-Level Analyses Using Real-Time Kinetic Labeling Couples Proliferation and Cell Death Mechanisms

Developmental Cell. 2019 Sep 25. PMID: 31564612

Researchers report on a versatile method for single-cell and population-level analyses using real-time Kinetic Labeling (SPARKL). SPARKL integrates high-content live-cell imaging with automated detection and analysis of fluorescent reporters of cell death. Compared to traditional methods of detection and analysis, SPARKL is more sensitive, accurate, and high throughput while substantially eliminating sample processing and providing richer data. This new technology can be applied to genetic, pharmacological, and small molecule discovery platforms. 

Rinku Jain, PhD, Aneel K. Aggarwal, PhD, et al.

Cryo-EM structure and dynamics of eukaryotic DNA polymerase δ holoenzyme

Nature Structural & Molecular Biology. 2019 Oct. PMID: 31582849

The survival of all organisms depends on their ability to faithfully duplicate their genome. DNA polymerase delta is the central enzyme that replicates the bulk of DNA in higher organisms, from yeast to humans. Taking advantage of recent advances in cryo-EM, the researchers are able to present for the first time a near atomic resolution structure of the complete enzyme in the act of DNA synthesis. As such, they are able to address longstanding questions about both the architecture and mechanism of this complex enzyme and its internal dynamics. The researchers uncover the basis of cancer and other disease mutations that modulate the activity of this central enzyme in maintaining genomic stability.

Hideo Watanabe, MD, PhD, et al.

Epigenomic profiling discovers trans-lineage SOX2 partnerships driving tumor heterogeneity in lung squamous cell carcinoma

Cancer Research. 2019 Sep 24. PMID: 31551362

Lung squamous cell carcinoma (LUSC)—the second most common histological subtype of lung cancer—has a poor overall 5-year survival rate and is a major cause of death worldwide. Researchers investigated super-enhancer (large clusters of putative enhancers in close genomic proximity) profiles in LUSC and identified a novel neural lineage signified by Sox2—the most commonly amplified oncogene in LUSC— and neural transcription factor Brn2. Identifying unique vulnerabilities of each LUSC lineage could lead to a novel approach to developing therapeutic strategies for this heterogeneous disease.

Jose Javier Bravo-Cordero, PhD, et al.

Textures of the tumour microenvironment 

Essays in Biochemistry. Oct 31 2019. PMID: 3165407

This review discusses how intravital microscopy has shed light into the dynamic nature of the tumor microenvironment (TME), revealing structural details of both tumor cells and other TME co-habitants in vivo, how these cells communicate with each other, and how they are organized in three-dimensional space to orchestrate tumor growth, invasion, dissemination and metastasis. The biology uncovered by imaging tumors in vivo holds promise in finding targets that can stop cancer spread by targeting the ‘textures’ of the TME.

 Emily Bernstein, PhD, et al.

 ATRX In-frame fusion neuroblastoma is sensitive to EZH2 inhibition via modulation of neuronal gene signatures

Cancer Cell. 2019 Oct 9. PMID: 31631027

 ATRX(Alpha Thalassemia/Mental Retardation, X-linked) is an epigenetic regulator mutated in pediatric and adult tumors. However, the consequences of ATRX alterations in cancer and on the epigenome remain ill defined. Focusing on the large structural variations of ATRX in neuroblastoma (NB), the researchers find that the consequent in-frame fusion (IFF) proteins lacking key chromatin-binding modules are altered in their genomic binding. ATRX IFFs localize to active promoters, notably that of REST, which encodes a neuronal transcriptional repressor. REST depletion and inhibition of EZH2 promote derepression of neuronal genes and cell death, suggesting cooperative pathways for silencing neuronal differentiation in ATRX IFF NB.  The studies supportEZH2 inhibitors as a therapeutic strategy to treat ATRX IFF NB patients, for which targeted treatment options are currently lacking. 

Emanuela Taioli, MD, PhD, Raja Flores, MD, et al.

Disparities in surgery for early-stage cancer: the impact of refusal

Cancer Causes & Control. 2019 Oct 19. PMID: 31630307

This study, which examined whether refusal of recommended surgical interventions might contribute to disparities in treatment, reports that more vulnerable patients are at higher risk of refusing recommended surgery and that this decision negatively impacts their survival. Patients refusing surgery were at increased risk of death compared to patients who underwent surgery.

Olga Rechkoblit, PhD, Aneel K. Aggarwal, PhD

Structural insights into mutagenicity of aniticancer nucleoside analog cytarabine during replication by DNA polymerase η

Scientific Reports. 2019 Nov 8. PMID: 31704958

Cytarabine (AraC) is the mainstay chemotherapy for acute myeloid leukemia (AML). While initial treatment with AraC is usually successful, most AML patients tend to relapse, and AraC treatment-induced mutagenesis may contribute to the development of chemo-resistant leukemic clones. The researchers show that whereas the high-fidelity replicative polymerase Polδ is blocked in the replication of AraC, the lower-fidelity translesion DNA synthesis (TLS) polymerase Polη is capable of promoting AraC induced mutations during chemotherapy.  To see how Polη promotes mutations, the researchers determined high-resolution crystal structures of human Polη with template AraC. Taken together, the structures provide a novel basis for the ability of Polη to promote AraC induced mutagenesis in relapsed AML patients.

Jian Jin, PhD, Kyle Butler, PhD, Xufen Yu, PhD

Dose-dependent activation of gene expression is achieved using CRISPR and small molecules that recruit endogenous chromatin machinery

Nature Biotechnology. 2019 Nov 11. PMID: 31712774

While gene expression can be activated or suppressed using CRISPR--Cas9 systems, tools that enable dose-dependent activation of gene expression without the use of exogenous transcription regulatory proteins are lacking. This article reports on chemical epigenetic modifiers (CEMs) designed to activate the expression of target genes by recruiting components of the endogenous chromatin-activating machinery, eliminating the need for exogenous transcriptional activators. The researchers show that CEMs upregulate gene expression at target endogenous loci up to 20-fold or more depending on the gene. They also demonstrate dose-dependent control of transcriptional activation, function across multiple diverse genes, reversibility of CEM activity, and specificity of best-in-class CEM across the genome.

Keith Sigel, MD; Yuxin Liu, MD, PhD; Michael Gaisa, MD, PhD

Recent trends in squamous cell carcinoma of the anus incidence and mortality in the United States, 2001-2015

Journal of the National Cancer Institute. 2019 Nov 19, PMID: 31742639

This study is the first to characterize and systematically compare contemporary national squamous cell carcinoma of the anus (SCCA) incidence trends by stage at diagnosis, birth year, and mortality. The data revealed a rise in SCCA incidence, particularly advanced stage disease, and a similar rise in mortality, suggesting the rise in SCCA incidence rates is real and not driven by increased screening in some populations. Dramatic increases in SCCA incidence were noted particularly in elderly women and young Black men. Findings call for future studies to identify reasons for the increase in SCCA incidence and mortality and improved prevention strategies.

 

Paz Polak, PhD, received grant funding from the V Foundation for Cancer Research for “The Genetic and Epigenetic Causes of BRCAness in Breast Cancer Patients of Caribbean origins and the Impact on Outcome.” The goal is to compare response to triple negative breast cancer treatment for African American, Caribbean American, and European American populations, investigate how frequently the BRCA1 gene is turned off in breast cancer patients of Caribbean origins, and use the information to inform the choice of targeted therapy for this population.

Julio Aguirre-Ghiso, PhD, received a Translational Research Award from METAvivor Research and Support Inc. for “Targeting Intrinsic and Immune Mechanisms in Persistent Dormant Cancer Cells in Stage IV Breast Cancer.” The project is focused on using novel blockers of survival pathways in dormant cancer cells to kill them and combine these new molecules with chemotherapy that targets proliferative lesions in stage IV cancer models. By eradicating dormant cancer cells (not targeted by chemotherapy) at the same time as targeting proliferative metastasis, the researchers anticipate significantly extending survival and delaying time to relapse in stage IV disease.

Josh Borgerding, research phase MD/PhD student at the Icahn School of Medicine at Mount Sinai, received a National Research Service Award (NRSA) Individual Predoctoral Fellowship for “Identifying Immune Mechanisms for Microbiota-inhibition of Anti-PD-L1 Tumor Response.” The project aims to dissect the microbiota-dependence of several immune compartments in B16 melanoma lesions treated with anti-PD-L1, provide a better understanding of how the intestinal microbiota regulates peripheral immune activity, and uncover possible mechanisms through which human microbial communities can be modified to improve cancer patient outcomes with immune checkpoint blockade therapy. Josh works in the laboratories of Jeremiah Faith, PhD, and Miriam Merad, MD, PhD.

Gabriele Varano, PhD, postdoctoral fellow in the laboratory of David Dominguez-Sola, MD, PhD,was awarded a Lymphoma Research Foundation (LRF) Postdoctoral Fellowship Grant for “Role of FOXO1 Mutations in the Pathogenesis of B-cell non-Hodgkin Lymphomas.”  The project aims to investigate how mutations targeting FOXO1 impact the biology of normal and transformed germinal-center (GC) B cells and contribute to B-cell lymphomagenesis.

Cardinale Smith, MD, PhD, Associate Professor and Director of Quality for Cancer Services, Mount Sinai Health System, was selected by Cambia Health Foundation as one of 12 emerging palliative care leaders for its Sojourn Scholar Leadership Program. Dr. Smith received two-year grant funding for “The Role of Implicit Bias on Outcomes of Minority Patients with Advanced Cancer.”

Andrea Branch, PhD, received The Shure Family Charitable Foundation award from Prevent Cancer Foundation for “Reversing Drivers of Liver Cancer: Focus on Inflammation and Repair.”

Nadejda Tsankova, MD, PhD, received R01 grant funding for “Crosstalk between EGFR and TEAD Activity Directs Migration in Human Glioblastoma.” This research is testing the potential therapeutic efficacy of YAP-TEAD inhibitors, with the expectation that pharmacologic inhibition of glioblastoma infiltrative growth will alleviate tumor burden while also blocking oncogenic RTK effects, thus offering new therapeutic options.

Zeynep H. Gümüş, PhD was granted a Department of Defense Lung Cancer Research Program (DOD LCRP) Concept Award for “Identifying mutational signatures of military carcinogens in lung adenocarcinomas of service members and veterans.” This research project utilizes whole-genome sequencing (WGS) to determine the full spectrum of genomic alterations in tumors of individuals with non-small cell lung adenocarcinoma (LAD) who were exposed to jet fuel during military service, with the goal of advancing prognostic and therapeutic potential.

 Julie Schnur, PhD, was awarded an NIH R25E grant titled “Training Cancer Care Providers to Implement Sensitive Practice Guidelines When Treating Adult Survivors of Sexual Violence: A Blended Learning Approach.” The goal of this project is to implement a training program for cancer care providers in sensitive practice techniques to reduce distress and retraumatization and increase feelings of safety and empowerment in survivors of sexual violence undergoing cancer screening and treatment. The program will be the first, cancer-focused, sensitive practice training program of its kind.

Bridget Marcellino, MD, PhD, was awarded a Research Training Award for Fellows (RTAF) from the American Society of Hematology. Dr. Marcellino is a graduate of the MD/PhD Program at the Icahn School of Medicine at Mount Sinai and completed her fellowship in Hematology and Medical Oncology at Mount Sinai. Dr. Marcellino is now an Assistant Professor of Medicine and Director of the Hematological Malignancies Tissue Bank for The Tisch Cancer Institute.

Marta Luksza, PhD, was one of 22 early-career researchers selected to join the Pew Scholars Program in the Biomedical Sciences. Dr. Luksza was awarded four years of funding to study how immune interactions drive the evolution of cancer and viruses.

Margaret H. Baron, MD, PhD, was awarded a renewal of her R01 grant, Regulation of Erythroid Cell Progenitors by the Nuclear Receptor Transcription Factor VDR. The funded studies may lead to the identification of novel molecular targets in erythroid progenitors that can be exploited to develop new therapies for anemias and other red cell disorders.

Jerry Chipuk, PhD, received a Melanoma Research Alliance Pilot Award, collaboratively funded by the Icahn School of Medicine at Mount Sinai, for “Mitochondrial Control of Melanoma Initiation.”

Jose Javier Bravo Cordero, PhD, received a grant award from the Adenoid Cystic Carcinoma Research Foundation for “Alternative Patient-Derived Xenograft in vivo model for Adenoid Cystic Carcinoma.” Mariana Brait, MSc, PhD, at Johns Hopkins Medicine, is co-principal investigator.

Jose Javier Bravo Cordero, PhD, is co-investigator on an R01 grant from the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. Ana Maria Cuervo, MD, PhD and Allan Wolkoff, MD, both with Albert Einstein College of Medicine, are the principal investigators. This collaborative grant with Albert Einstein researchers utilizes high-resolution intravital imaging and superresolution microscopy techniques in the Bravo-Cordero Lab at Mount Sinai in the context of liver disease.

Hideo Watanabe, MD, PhD, received a Lung Cancer Research Program Career Development Award from the Department of Defense for “Exploring the link between lung cancer lineage heterogeneity and microenvironment.” The research aims to identify different lineage state subclasses of lung cancers that interact with their neighboring cells, increase understanding of the interaction mechanisms, and examine how dynamic changes within the tumor can occur during the course of cancer development and response to treatment. The interaction at the molecular level between lung cancer cells and surrounding cells in the microenvironment may provide a target for therapeutic intervention.

Julio Aguirre-Ghiso, PhD, received renewed funding from the Samuel Waxman Cancer Research Foundation for his research on preventing metastasis by targeting dormant disseminated tumor cells.  Continued research will include a focus on the relationship of the immune microenvironment during early and late stages of cancer progression.

James J. Bieker, PhD, and Jeffrey Glassberg, MD, were recipients of the 2019 Sickle Cell Disease/Advancing Cures Award, funded by the Doris Duke Charitable Foundation. Their research project is titled: Quantitative Modulation of an Erythroid Regulator as a Novel Genetic Target for Sickle Cell Disease. Gene therapy for sickle cell disease (SCD) has become a reality, with several patients cured and many clinical trials underway. Current approaches to SCD gene therapy still require ex vivo editing and chemotherapy with related concerns about toxicity and long-term engraftment. Drs. Bieker and Glassberg are conducting a series of preclinical experiments to explore a new approach to curing SCD that has the potential to overcome the current drawbacks of SCD gene therapy.

David Dominguez-Sola, MD, PhD and Peter Heeger, MD were awarded an R01 for “Decay Accelerating Factor and B cell Immunity.” They are studying a previously unappreciated link between germinal centers and the complement pathway—a complex system of proteins with ancestral and ancillary roles in inflammation. The results have the potential to guide second order studies aimed at exploiting the complement/B cell axis to either inhibit development of pathogenic B cell responses (e.g., in transplantation or autoimmunity) or augment B cell response (e.g., in response to vaccines).

Robert Samstein, MD, PhD, received an NIH Director’s Early Independence Award for “Dissecting the Influence of DNA Damage Response and Homologous Recombination Deficiencies on Tumor Immungenicity.” His research focuses on elucidating the role of DNA damage repair and response pathway in altering a tumor’s ability to be recognized and attacked by the immune system.

Maria Soledad Sosa, PhD, received a Career Development Award from the Melanoma Research Foundation to develop a therapeutic strategy to keep disseminated cancer cells (DCCs) in a dormancy phase by blocking Midkine, which acts as a reactivation signal, and inducing dormancy signals via the transcription factor NR2F1. The goal is to stop DCCs from forming live-threatening metastases. Dr. Sosa is conducting this research under the mentorship of María S. Soengas, PhD, with CNIO, Spain.

Yelena Z. Ginzburg, MD, was one of just seven recipients of highly competitive research funding from the MPN Challenge Grant program, a partnership between the MPN Research Foundation and the Leukemia & Lymphoma Society. Dr. Ginzburg’s project, “Dysregulated iron metabolism plays a pivotal role in polycythemia vera,” aims to investigate how iron deficiency develops in polycythemia vera, how erythropoiesis persists at a high rate despite iron deficiency, whether iron metabolism is differently regulated in JAK2 mutated erythroblasts, and if JAK2 mutant bone marrow cells exhibit a competitive advantage during transplants. 

Hideo Watanabe, MD, PhD, was awarded R01 grant funding from the NCI for “Lineage Heterogeneity and Plasticity in Lung Cancer.” With this grant funding, Dr. Watanabe and his team aim to improve the precision of lung cancer diagnostics and therapeutics by investigating the roles of novel lineage factors that define unique subgroups. By determining the heterogeneity and dynamics of lineage states at a single cell level, they aim to understand how lineage can switch within a tumor. They will test their hypothesis that the degree of heterogeneity correlates with the plasticity of the tumor and aggressive tumor behaviors. Results will enable them to evaluate the potential of inducing transdifferentiation as a therapeutic strategy.

Jerry Chipuk, PhD , received a Melanoma Research Alliance Pilot Award, collaboratively funded by the Icahn School of Medicine at Mount Sinai, for “Mitochondrial Control of Melanoma Initiation.”

Miriam Merad, MD, PhD, received the 2018 William B. Coley Award for Distinguished Research in Basic Immunology in recognition of her groundbreaking contributions relating to the biology of macrophages and dendritic cells, including defining their roles in the context of immunotherapy and tumor development. Dr. Merad leads the cancer immunology program at The Tisch Cancer Institute.

Dr. Merad also received a Senior Faculty Award from the Icahn School of Medicine at Mount Sinai at the Annual Faculty Council Awards Ceremony.

Arvin Dar, PhD, received a Junior Faculty Award from the Icahn School of Medicine at Mount Sinai at the Annual Faculty Council Awards Ceremony.

Samuel Waxman, MD, Distinguished Service Professor, Icahn School of Medicine at Mount Sinai, and founder and CEO of the Samuel Waxman Cancer Research Foundation, received the "Friendship Award" from the People's Republic of China in recognition of more than 30 years of U.S.-China scientific cooperation for cancer research and the successful development of a treatment for acute promyelocytic leukemia that now has a greater than 90% cure rate.

Mount Sinai’s Multiple Myeloma Program, Sundar Jagannath, MD, Director, received the 2018 Multiple Myeloma Research Consortium (MMRC) Accelerator Award from the Multiple Myeloma Research Foundation (MMRF) in recognition of exceptional contributions to the rapid initiation and completion of clinical trials supported through the MMRC as well as leadership in the consortium and innovative clinical translational efforts in the areas of immune biology and myeloma genomic data analysis and validation.

Janice L. Gabrilove, MD, FACP, was appointed to the Board of Directors of the Leukemia and Lymphoma Society (LLS). She previously served on the review committees for the LLS Career Development Program and the LLS Scholar Awards. Dr. Gabrilove has two patented discoveries which have significantly impacted outcomes for patients with hematologic malignancies: arsenic trioxide formulation, a curative therapeutic for acute promyelocytic leukemia, and human granulocyte colony stimulating factor, or G-CSF (neupogen/neulasta), which has enabled development of curative therapies including the use of peripheral blood progenitor cell transplantation. Dr. Gabrilove is The James F. Holland Professor of Medicine and Oncological Sciences, Associate Director of Education and Training at The Tisch Cancer Institute, and Director of Clinical Research Education Programs for the Icahn School of Medicine at Mount Sinai.

Margaret H. Baron, MD, PhD, was named chair of the Molecular and Cellular Hematology (MCH) Study Section of the National Institute of Health (NIH), which reviews applications involving both basic and applied aspects of normal and abnormal hematopoiesis. Dr. Baron is the Fishberg Professor of Medicine, Senior Associate Dean for Education, and Director of the MD-PhD Program. She is also Professor of Oncological Sciences and Professor of Cell, Developmental & Regenerative Biology. Dr. Baron has nearly 30 years of continuous, independent NIH-sponsored research funding in developmental hematopoiesis.

Adriana K. Malone, MD, Assistant Professor of Medicine, Hematology and Medical Oncology, and Medical Education, was selected as one of 12 participants in the 2018-2019 Education Scholars Program through the American Society of Clinical Oncology (ASCO). The year-long program imparts expertise in the design of education activities and leadership skills aimed at enhancing the ASCO learning portfolio and overall medical education.

Susan Boolbol, MD, was honored with the American Cancer Society’s 2017 Mother of the Year award in recognition of her community service and contributions to cancer control.

Ronald Hoffman, MD, Director of the Myeloproliferative Disorders Research Program, was honored with the 2017 American Society of Hematology (ASH) Mentor Award for decisively shaping the careers of 33 physicians, physician-scientists, and basic scientists, thereby advancing research and patient care.

Dr. Hoffman is the first Mount Sinai hematologist to receive this prestigious award. Dr. Hoffman is senior editor of the textbook Hematology: Basic Principles and Practice,

Amy Tiersten, MD, Clinical Director of Breast Medical Oncology at The Mount Sinai Hospital, was recognized by the Dubin Breast Center at its 2018 annual benefit for her commitment to breast cancer research.

The Tisch Cancer Institute, the Icahn Institute for Genomics and Multiscale Biology, and the Department of Genetics and Genomic Sciences hosted a Cancer Precision Medicine Retreat under the leadership of Adam Margolin, PhD, and Ramon Parsons, MD, PhD, on May 25, 2018.

Links to all the sessions

Stephanie V. Blank, MD, was named Director of the Division of Gynecologic Oncology for the Mount Sinai Health System Department of Obstetrics, Gynecology and Reproductive Science. She is also Fellowship Director for Gynecologic Oncology.

Peter R. Dottino, MD, was named Vice-Chair of Clinical Affairs for the Department of Obstetrics, Gynecology and Reproductive Science, and Executive Director of the The Blavatnik Family – Chelsea Medical Center at Mount Sinai.

Emily Bernstein, PhD, was named Coleader of the Cancer Mechanisms Research Program. Dr. Bernstein and fellow coleader Julio A. Aguirre-Ghiso, PhD, facilitate basic research on genetic, biochemical, and developmental pathways that drive cancer initiation and progression, and foster intra- and inter-program collaborations that accelerate the development of novel, targeted therapies.

Samir Parekh, MD, was named Director, Multiple Myeloma Translational Research. He directs translational research for identification of biomarkers and new drug development across the spectrum of patients with multiple myeloma.

TCI launched a summer research fellowship program for first year medical students who have not yet had extensive research experience. The fellowship supports original cancer research under the tutelage of a faculty mentor intended to lead to a scholarly research year between the student’s third and fourth years.

A Clinical Exposure Program was initiated for students in the Cancer Biology concentration of the PhD in Biomedical Sciences Program at the Graduate School of Biomedical Sciences at the Icahn School of Medicine The goals of the program are for students to (1) gain insight and motivation from interactions with patients; (2) learn to communicate about their research in lay-friendly language; and (3) gain a better understanding of clinical disease manifestations and treatment plans.

Adam Margolin, PhD, an internationally-renowned computational biologist, joined Mount Sinai as Chair and Professor of the Department of Genetics and Genomic Sciences, Director of the Icahn Institute for Genomics and Multiscale Biology, and Senior Associate Dean for Precision Medicine at the Icahn School of Medicine.

Fred R. Hirsch, MD, PhD, an internationally-renowned authority on lung cancer treatment and research, joined Mount Sinai as the Joe Lowe and louis Price Professor of Medicine, Hematology and Medical Oncology; Executive Director of the newly-created Center for Thoracic Oncology in The Tisch Cancer Institute; and Associate Director of Biomarker Discovery for The Tisch Cancer Institute. His research, spanning more than 25 years, has helped identify and validate prognostic and predictive markers for lung cancer outcomes and predictive markers for personalized lung cancer therapies, and also involves biomarkers for early detection of lung cancer.

Edward M. Wolin, MD, joined Mount Sinai as Director of the Center for Carcinoid and Neuroendocrine Tumors. An internationally-renowned authority on these tumors, known as NETs, Dr. Wolin has pioneered innovative therapies with novel somatostatin analogs, mTOR inhibitors, anti-angiogenic drugs, and peptide receptor radiotherapy.

Peter Wiklund, MD, PhD, world-renowned surgeon who pioneered robot-assisted cystectomy, was appointed by the Department of Urology as Director of the Bladder Cancer Program at Mount Sinai. Dr. Wiklund has extensive experience in advanced oncological surgery in patients whose tumor is growing on several pelvic organs.

J. Jaime Alberty, MD, FACS, joined Mount Sinai as Assistant Professor of Surgery, Division of Breast Surgery. He sees patients at the Dubin Breast Center, Mount Sinai Queens, and The Blavatnik Family – Chelsea Medical Center at Mount Sinai. Dr. Alberty has extensive experience in breast ultrasonography, sentinel lymph node biopsy, and nipple and areola-sparing mastectomies. As a "Hidden Scar" certified surgeon, he employs a number of oncoplastic techniques during his breast cancer operations.

Madhuri Devabhaktuni, MD, joined Mount Sinai as Assistant Professor of Medicine, Hematology and Medical Oncology. She sees patients at Mount Sinai St. Luke’s and was instrumental in establishing an infusion center there.

Marta Luksza, PhD, joined Mount Sinai as an Assistant Professor of Oncological Sciences. Dr. Luksza and collaborators created the first mathematical model to predict how a cancer patient will respond to immunotherapy, as reported in Nature.

Mobile Mammography

Mount Sinai’s Mammography Van, funded through a grant from New York State to provide women with access to breast cancer screening in their communities, began operations under the leadership of Laurie Margolies, MD, in October 2018.

New Infusion Centers

The Mount Sinai St. Luke’s Infusion Center opened in 2018. Serving the Upper West Side community, the unit provides chemotherapy, intravenous medications for benign hematologic conditions, therapeutic infusions for rheumatologic disorders, and blood transfusions.

The Mount Sinai Brooklyn Ambulatory Infusion Center opened in 2018. Under the leadership of Stefan Balan, MD, the unit supports oncology expertise, innovative cancer treatment, and clinical trials in a close-to-home treatment center for residents of Brooklyn.

New Unit for Immunocompromised Children

The Jack Martin Fund Inpatient Unit for Children’s Cancer and Blood Disease opened at Kravis Children’s Hospital at Mount Sinai.

Personalized Vaccine

A patient received, for the first time at Mount Sinai, a personalized vaccine regimen to prevent cancer recurrence. TCI has a state-of-the-art vaccine and cell therapy lab that is producing and testing the efficacy of these types of patient-specific vaccines for cancer. Nina Bhardwaj, MD, PhD, Professor of Medicine, Hematology and Medical Oncology, and Co-leader of the TCI Cancer Immunology Research Program, directs the lab and the highly-integrated immunotherapy program focused on harnessing the immune system against cancer. Dr. Bhardwaj collaborated closely on this first vaccine with Eric M. Genden, MD, Professor and Chair of Otolaryngology, attending physician to the patient with head and neck cancer. The vaccine therapy protocol is part of TCI’s Novel Therapeutics Program, under the direction of Matthew Galsky, MD.