Cancer Discovery. 2021 Jul 23. PMID: 34301793
Dr. Parsons, Dr. Jin, and team report on compelling data supporting MS21, an engineered molecule, as a potent, selective, and highly efficient degrader of the enzyme AKT that is overly active in many cancers. Among their findings was that degradation of AKT led to effective inhibition of downstream signaling and the identification of a new AKT substrate phosphoprotein—AURKB—that is required for cell viability. The study lays a solid foundation for the clinical development of an AKT degrader for the treatment of human cancers with PIK3CA, PTEN, HER2 and AKT1 alterations based on the premise that MS21 can selectively degrade phosphorylated but not unphosphorylated AKT.
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"On the cover: During germinal center (GC) responses, positive selection by T follicular helper (Tfh) cells is essential for the clonal expansion and differentiation of B cells. Roberto, Varano, et al. found that mutations targeting the transcription factor FOXO1, commonly found in GC-derived B cell lymphomas, activate cell-intrinsic programs that mimic positive selection and support competitive expansion of mutant B cells. Such capacity for mimicry is illustrated by an artificial flower built from toy bricks that copycats two positively selected GC B cells—a fully blossomed echinacea flower and a blossoming young echinacea, circled by bumblebees (Tfh cells)—found among a myriad of non-selected B cells (flowers that did not bloom). Cover art by David Dominguez-Sola, based on discussion with Yukie Takabatake"
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Cancer as a specialty at The Mount Sinai Hospital saw a significant improvement in its ranking by U.S. News & World Report, from 49 in 2020 to 32 in 2021. In tandem with the improved ranking, our reputation score for cancer—a component of the ranking—was higher in 2021 than it has been since 2016. U.S.
News & World Report also rated The Mount Sinai Hospital—ranked among the top 20 hospitals in the nation—as “High Performing” in 13 conditions and procedures, including colon cancer surgery and lung cancer surgery.
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Jacques Azzi, MD, has joined the faculty as Assistant Professor of Medicine (Hematology and Medical Oncology). His clinical focus is on hematologic malignancies, with a particular emphasis on bone marrow transplant; he will see patients at the Ruttenberg Treatment Center. Dr. Azzi completed fellowships in Stem Cell Transplant and Cellular Therapy at the Icahn School of Medicine at Mount Sinai, and in Hematology/Oncology at New York University Grossman School of Medicine, where he served as Chief Fellow. He did his residency training in Internal Medicine at Staten Island University Hospital. Dr. Azzi did an internship in Internal Medicine at Saint George Hospital University Medical Center in Beirut after earning his MD at University of Balamand Medical School, also in Beirut, and spent a year as a postdoctoral research fellow at MD Anderson Cancer Center. |
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Jonathan Feld, MD, has joined the faculty as Assistant Professor of Medicine (Hematology and Medical Oncology). He will see patients with hematologic malignancies, particularly myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), at the Ruttenberg Treatment Center. Dr. Feld completed his fellowship in Hematology and Medical Oncology at the Icahn School of Medicine at Mount Sinai and residency in Internal Medicine at Beth Israel Deaconess Medical Center/Harvard Medical School in Boston. He earned his MD at Albert Einstein College of Medicine of Yeshiva University. Dr. Feld has conducted translational research on MDS and the immune microenvironment, as well as clinical research projects in AML. He is working on novel therapeutic development in MDS and AML, with a focus on patients who are relapsed/refractory to hypomethylating agents. |
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Keith Sigel, MD, PhD, is a co-principal investigator on a newly awarded grant from the National Cancer Institute for a large-scale study to evaluate anal cancer screening in high-risk women who have been previously diagnosed with human papillomavirus (HPV) infection. This multi-center study is a collaboration between the Mount Sinai Anal Dysplasia Screening Program, The University of Texas MD Anderson Cancer Center, and The University of Texas Health Science Center at Houston (UTHealth). The five-year trial will evaluate the effectiveness of anal cancer screening interventions for women who are not infected with HIV and who have a history of HPV-related precancers in the lower genital sites, a population with the largest group of anal cancers in the United States.
Elizabeth Yu Chiao, MD, MPH, Professor of Epidemiology and General Oncology at MD Anderson, and Ashish A. Deshmukh, PhD, MPH, Assistant Professor of Management, Policy & Community Health at UTHealth School of Public Health in Houston, are the other co-principal investigators.
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Doris Germain, PhD has obtained a supplement to one of her current R01 grants—“Understanding the role of mitochondial UPR-activating mtDNA landscapes in health and longevity,” which focuses on the link between mitochondrial genetics, cancer susceptibility, and aging. Her research team helped to pioneer the understanding of mitochondria-nucleus retrograde signaling, leading to the discovery of the mitochondrial unfolded protein response (UPR). Dr. Germain’s lab uses a unique mouse model by which mice that share the same nuclear genome but have different mitochondrial genomes are compared. Her recently-awarded supplement uses the same mouse model to investigate her hypothesis that mitochondrial genetics may explain why some individuals are asymptomatic, while others develop severe symptoms upon infection with COVID-19. This work is being conducted in collaboration with the laboratory of Ana-Fernandez-Sesma, PhD, and the laboratory of Adolfo Garcia-Sastre, PhD, in the Department of Microbiology.
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For junior faculty at the rank of assistant professor with a focus on immunology, immunotherapy, genetics, or cell biology.
Letter of Intent due date: September 8.
Pre-eligibility questionnaire due date: September 6
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Congratulations to Sheryl Green, MBBCh, on her promotion to Professor at the Icahn School of Medicine at Mount Sinai. Dr. Green is an outstanding clinical investigator with a well-established national reputation, especially in technology development and quality of care. She has established new programs and advanced novel technologies such as prone breast treatment, deep inspiration breath hold technique, intraoperative radiation therapy, stereotactic radiosurgery, and intracoronary brachytherapy; her research has led to new standards of care for these treatments. Dr. Green is a national leader in improving the quality of life of women undergoing breast cancer treatment. Additionally, she is a skilled educator and has won numerous teaching awards.
Dr. Green received her medical degree from the University of Witwatersrand Medical School in Johannesburg, South Africa. She came to the Department of Radiation Oncology at Mount Sinai in 1995 as a resident and joined the faculty in 1998.
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TCI was selected by The American Society of Clinical Oncology (ASCO) and the Association of Community Cancer Centers (ACCC) as one of 75 research sites to participate in a pilot project testing a self-assessment tool and an implicit bias training program focused on increasing racial and ethnic diversity among clinical trial participants.
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For the second year, TCI hosted “Oncology Week” for high school students enrolled in the Center for Excellence in Youth Education Medical and Scientific Exploration and Sherman Scholar Programs. Organized and led by Dan Hasson, PhD, Assistant Professor, Oncological Sciences and Dermatology, and Co-Director of the TCI Bioinformatics Core for Next Generation Sequencing (BiNGS), the week-long online forum exposed participating students to a broad spectrum of multidisciplinary cancer research, including basic research and community-engaged research to advance equity and reduce disparities. TCI scientists and clinical investigators shared unique perspectives on how they deconstruct and tackle cancer; students authored and presented outstanding introductions for each presenter. The students learned about tools for imaging cancer cells, to better understand how they behave; tiny animal models, including the fly and zebra fish, to advance therapeutic discovery; the genetics of cancer and how genes can be advantageously manipulated; and improving health via genetic big data and clinical trials.
TCI members interested in engaging an enthusiastic student in their lab for a year-long or summer placement are invited to contact Dr. Janice Gabrilove or Dr. Hasson. |
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Nature Communications. 2021 Aug 3. PMID: 34344863
Dr. Irie, Dr. Reddy, and colleagues identified a potent multi-kinase inhibitor of cancer stem cells—108600—that suppresses the growth of triple negative breast cancer (TNBC), overcomes resistance to chemotherapy, and is effective against established metastatic disease. Findings support the clinical translation of 108600 to clinical trials, with the potential of dramatically improving morbidity and mortality associated with TNBC.
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Gut. 2021 Jul 28. PMID: 34321221
This study highlights complex, heterogeneous, non-coding and unannotated small RNA expression signatures from payloads of circulating extracellular vesicles. The researchers identified unannotated biomarkers capable of accurately detecting early-stage hepatocellular carcinoma (HCC). Findings support the prospect of a minimally invasive, blood-only HCC surveillance biomarker.
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Immunity. 2021 Aug 10. PMID: 34380064
Understanding the precise mechanistic contribution of genetic alterations to cancer pathogenesis is critical to define better clinical stratification and therapeutic strategies. A majority of B-cell non-Hodgkin lymphomas (B-NHLs) originate from germinal center (GC) B cells, which are essential for the generation of antibodies during immune responses. The researchers examined how mutations in FOXO1 (forkhead box O1) found in B-NHLs impact normal and tumoral GC B-cell phenotypes. They found that these mutations encode for partially hypomorphic protein variants that mimic signaling and transcriptional features of positively selected B cells. Such mimicry favors the competitive expansion of FOXO1 mutant B cells during GC responses and lymphomagenesis.
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Haematologica. 2021 Jun 1. PMID: 32354874
This paper reports on the results of Part 2 of the PAVO study, evaluating a concentrated, pre-mixed co-formulation of daratumumab and recombinant human hyaluronidase PH20 (rHuPH20)—DARA SC—which has a short (3-5 minutes) subcutaneous administration time. Deep and durable responses were observed, supporting ongoing studies investigating DARA SC in multiple myeloma and other conditions.
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Journal of the American Chemical Society. 2021 Jun 16. PMID: 34100597
Dr. Jian Jin, Dr. Wenyi Wei at Harvard, and team developed a novel technology—TF-PROTACs—for degrading transcription factors (TFs) by hijacking the cellular ubiquitin-proteasome system. This technology provides a generalizable platform to achieve selective degradation of TFs, many of which are oncogenic proteins, and a universal strategy for targeting most “undruggable” TFs.
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Journal of Clinical Oncology. 2021 Jun 2: PMID: 34077237
This trial demonstrated a viable and promising strategy for patients with esophageal and esophagogastric junction adenocarcinoma that incorporates induction chemotherapy prior to chemoradiation and the utility of early response assessment using positron emission tomography as a biomarker to individualize subsequent treatment.
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The Lancet Haematology. 2021 Aug 8. PMID: 34329580
The authors review the evidence behind the contemporary approach to risk stratification and treatment of polycythaemia vera—a difficult disease to study due to its rarity and long disease course—and discuss frameworks for using data more efficiently, constructing more nuanced prognostic models, and overcoming challenges in clinical trial design.
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Findings describe a novel mechanism mediating the shift from a proliferative to an invasive phenotype in BC cells in vivo and identify srGAP1 as a mediator of this phenotypic switch through a TGFβ2 signaling axis.
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Save the Date: Service of Remembrance |
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Memorial Service
The Mount Sinai Health System Bereavement Committee will hold its annual system-wide memorial service on October 5 at 6 pm and October 14 at 12 noon to remember and celebrate the lives of cancer patients who passed away this year. Recognizing that many staff members have dealt with immense loss this year due to COVID-19 and other causes, the committee invites staff who have lost a loved one this year and would like their loved one honored at the service to email MemorialServiceRSVP@mountsinai.org.
ID: 874 8148 8091
Passcode: 051851
Phone: 929-436-2866
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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.
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Ramon Parsons, MD, PhD, Director
Janet Aronson , Editor
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