Scott Friedman, MD, Dean for Therapeutic Discovery and Chief of the Division of Liver Diseases at the Icahn School of Medicine at Mount Sinai, has been awarded a new R01 grant for liver cancer research from the National Institute of Diabetes and Digestive and Kidney Diseases . With this five-year award, Dr. Friedman will have had 40 years of continuous R01 funding from the National Institutes of Health, complementing a groundbreaking and highly productive research career
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This new grant supports research on chronic non-alcoholic steatohepatitis (NASH) of the liver—the fastest-rising cause of primary liver cancer development, which affects millions of individuals worldwide. The funded research aims to clarify the role of hepatic stellate cells (HSCs) in the pathogenesis of NASH and hepatocellular carcinoma (HCC). Using models of HSC depletion and a murine NASH model developed by Dr. Friedman and team, and based on the hypothesis that activated and senescent HSCs in NASH express unique drivers that contribute to a tumor-prone stromal microenvironment, the team will investigate the dynamics and unique contributions of HSCs to NASH and the stromal abnormalities they generate that give rise to HCC. The research is expected to address how inflammation and hepatic fibrosis create a pro-carcinogenic stroma that promotes the development of HCC even without co-existent cirrhosis. It will yield new insights into HSC biology in health and disease and link abnormalities from mouse models to human NASH-HCC to establish their clinical relevance as therapeutic targets, thereby advancing an understanding of how to prevent and treat liver fibrosis and cancer in patients with NASH.
Dr. Friedman’s previous R01-funded research on liver fibrosis cancer has resulted in significant findings that have informed advancements in patient care and outcomes, including:
- Isolation and characterization of hepatic stellate cells (HSCs) in rodent and human liver
- Established the concept of HSC “activation,” the transdifferentiation from quiescent HSCs to fibrogenic myofibroblasts, which underlies fibrosis in parenchymal liver disease (e.g., viral hepatitis, alcoholic and non-alcoholic steatohepatitis and others)
- Discovery of platelet-derived growth factor (PDGF) and transforming growth factor beta 1 (TGFb1) signaling pathways as major drivers of stellate cell activation
- Regulation of HSC activation by immune cells and their secreted products
- Fueling of HSC activation by autophagy and the unfolded protein response
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Cloning and characterization of the Krüppel-like factor 6 (KLF6) gene, which regulates HSC activation and also is a novel tumor suppressor gene whose inactivation contributes to carcinogenesis in many tissues
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New Investigator-Initiated Research Incubator |
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The Cancer Clinical Investigation Program, under the leadership of Karyn Goodman, MD, MS, has launched an Investigator Initiated Research Incubator designed to foster new ideas, facilitate connections, and accelerate innovative science from concept to reality. The incubator is distinctly formatted as a monthly round table for spontaneous discussion about early clinical trial concepts, funding mechanisms, and new research collaborations. It provides mentorship and access to a broad and diverse set of perspectives, including commercial partners. This medium is unlike any other in that it offers a rich environment for ideas to emerge and mature, giving them a better chance to succeed.
The incubator is one component in a larger initiative by Dr. Goodman to advance investigator-initiated cancer clinical trials (IITs). Concepts that mature within the incubator may be considered by a newly established IIT-Review Committee for feasibility, provision of in-kind protocol development support and regulatory affairs expertise, and possible seed funding. The IIT Incubator Concept Sheet can be found on the TCI Clinical Research Intranet Webpage.
Investigators who seek to translate a moment of questioning into actual, real-world practice are highly encouraged to participate. Contact [email protected] to be added to the email distribution list for notification about future sessions. |
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Maria Soledad Sosa, PhD, was awarded a 2021 Breast Cancer Alliance Young Investigator Award for “Targeting disseminated breast cancer cells to prevent metastasis.” Pre-malignant breast cells are able to disseminate to target organs, and after an extended dormancy phase they reawaken and are the main contributors to metastases in a HER2-positive breast cancer mouse model.
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Based on the belief that reactivation of early disseminated cancer cells (DCCs) requires interactions with late arriving DCCs derived from primary tumors, Dr. Sosa aims to decipher the mechanisms behind these interactions to provide a framework for designing targeted therapies. |
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Brian Brown, PhD, has received the Investigator Award from Alliance for Cancer Gene Therapy to advance a promising immunotherapy approach to fight lung cancer. As part of the natural immune system, macrophages typically protect patients from infections, but tumors can reprogram macrophages to suppress other immune system cells and keep them from killing cancer cells. Dr. Brown aims to stop this behavior by equipping a patient's own T cells to kill immune-suppressing macrophages in tumors. This strategy—rooted in the success of CAR T-cell therapy—is designed to develop a new CAR that specifically kills macrophages in tumors while sparing them in healthy tissue. Even though Dr. Brown’s research targets lung cancer, the approach may be effective in treating many different types of cancers.
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Julie Di Martino, PhD, associate scientist in the laboratory of Javier Bravo-Cordero, PhD, was awarded a grant from METAvivor, a non-profit organization that funds vital research to help improve the longevity and quality of life for patients with metastatic breast cancer. Dr. Di Martino’s research is aimed at understanding the role of the bradykinin pathway in breast cancer dormancy to inform strategies that target disseminated cells in patients with advanced breast cancer. |
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- LCRF-AstratZeneca Grant Program, Letter of Intent Due Date: April 30
- LCRF Pilot Grant Program, Letter of Intent Due Date: April 30
- Research Grant on Disparities in Lung Cancer, Letter of Intent Due Date: May 7
Letter of Inquiry Deadline: August 2
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Ronald H. Hoffman, MD, Director of the Myeloproliferative Disorder Research Program at TCI, has been selected as a 2021 recipient of the Jacobi Medallion. Awardees have made exceptional contributions to the Icahn School of Medicine at Mount Sinai, the Mount Sinai Health System, The Mount Sinai Alumni Association, or the fields of medicine or biomedicine.
A virtual award ceremony will be held on June 22.
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“TCI’s experience in cancer research and treatment was invaluable in confronting COVID-19. Our scientists helped improve the reliability of Mount Sinai’s successful ELISA antibody test for SARS-CoV-2. Our hematologists helped Mount Sinai quickly institute an anticoagulation protocol for patients with COVID-19 whose mortality was often tied to untreated blood clots. Our immunologists, familiar with high cytokine release levels in cancer patients, applied their knowledge to critically ill COVID-19 patients with similar reactions. We launched the nation’s first study on allogeneic stem cell therapy in COVID-19 patients with overactive immune responses.”
Excerpted from the Director's Message
Read about some of TCI's extraordinary accomplishments during the most challenging of years. 2021 Specialty Report
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Nature Cancer. 2021 Mar 11.
This paper reports on new findings about the role of the bone marrow (BM) perivascular niche in breast cancer (BC)-disseminated tumor cell (DTC) dormancy. The data reveal a specific BM cell type—NG2+/Nestin+ MSCs—which maintains both hematopoietic stem cell (HSC) and DTC dormancy, and the mechanisms behind this biology. The data provide direct proof that HSC dormancy niches control BC DTC dormancy and suggest that aging or extrinsic factors that affect the NG2+/Nestin+ MSC niche homeostasis may result in a break from dormancy and BC bone relapse. Findings support that when the microenvironment is negatively altered or damaged it loses its metastasis suppressing function.
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Oncologist. 2021 Mar 5. PMID: 33675133
This paper reports on a nonrandomized phase II trial for early-stage human papillomavirus-related oropharyngeal squamous cell carcinoma. Data indicate that transoral robotic surgery followed by no or reduced-dose radiotherapy based on pathologic staging results in favorable survival with excellent function for carefully selected patients.
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eLife. 2021 Feb 11. PMID: 33570494
This paper reports on data derived from unbiased global sequencing and genetic approaches that suggests the existence of a unique macrophage cell type with novel cell surface biomarkers and the importance of erythroid Krüppel-like factor (EKLF)/KLF1 in its identity. The studies provide a detailed perspective on the importance of EKLF in the establishment of the dynamic gene expression network within erythroblastic islands in the developing embryo and the means for their efficient isolation.
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Cancer. 2021 Mar 8. PMID: 33682111
This paper reports on an analysis of demographic information from 21 cancer clinical trials leading to FDA approvals. The analysis revealed that clinical trials conducted primarily outside the U.S. were two times less likely to enroll Black participants than trials conducted in the U.S. Findings suggest that globalization of cancer clinical trials may have the unintended consequence of further exacerbating existing racial disparities in cancer clinical trial representation and ultimately the generalizability of trial results.
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Cancer. 2021 Feb 25. PMID: 33629759
This paper reports on factors that distinguish liver cancer in Black patients in the U.S., with a focus on patients with hepatitis-C (HCV) infection. The researchers examined liver function and the presence of cirrhosis at the time of diagnosis and whether hepatocellular carcinoma (HCC) in Black patients was associated with a more aggressive phenotype, leading to increased mortality. Findings indicate that Black patients with HCV develop HCC at earlier stages of liver disease than other racial groups and that their tumors often carry worse prognostic features. This suggests that HCV-exposed Black patients may benefit from liver cancer surveillance even if they do not have cirrhosis.
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Nature Reviews Clinical Oncology. 2021 Feb 12. PMID: 33580222
In this review, the authors describe the current role of PD-L1 immunohistochemistry assays used to inform the selection of patients to receive anti-PD-1 or anti-PD-L1 antibodies. They discuss the various technical and clinical challenges associated with these assays, and provide perspective on how to optimize PD-L1 as a biomarker to best predict which patients with solid tumors may benefit from these drugs.
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Christos Adamopoulos, PhD; Tamer Ahmed, PhD; Zoi Karoulia, PhD; Angelo Amabile, PhD; Xuewei Wu, PhD; Stuart Aaronson, MD; Celina Ang, MD; Brian Brown, PhD; Avner Schlessinger, PhD; Poulikos Poulikakos, PhD; et al.
Cancer Discovery. 2021 Feb 10. PMID: 33568355
This work identifies a new class of RAF inhibitors that are selective for dimeric over monomeric BRAF, and determines the basis of their selectivity. The research demonstrated that a rationally-designed combination of RAF and MEK inhibitors, based on their conformation selectivity, achieved increased efficacy and high therapeutic index when used to target BRAF(V600E) tumors.
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Nature Reviews Cancer. 2021 Feb 10. PMID: 33568791
This comprehensive review addresses the normal and cancer-associated functions of histone variants and histone chaperones as tumor-promoting or tumor-suppressive players in the pathogenesis of cancer and potential therapeutic avenues. Discussion is focused on members of the diverse H2A and H3 histone variant families, including H2A.Z, macroH2A, H3.3 and centromeric protein A (CENP-A), where a strong body of evidence for their involvement in solid tumors is available.
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Nature Cancer. 2021 Mar 1.
Cyclin-dependent kinases (CDKs) 4 and 6 inhibitors (CDK4/6is) are effective in metastatic breast cancer, but they have been only modestly effective in most other tumor types. This research uncovers a general mechanism of intrinsic resistance to CDK4/6is and CDK4/6i-derived degraders and the need for new inhibitors targeting the CDK4/6i-resistant, thermostable form of CDK6 for application as cancer therapeutics. The data indicate that a low ratio of CDK6 to CDK4 expression in the tumor may be used to stratify patients who are likely to benefit from CDK4/6-based therapies. Findings suggest that for patients with low CDK6 relative to CDK4 expression, combinations of CDK4/6is or CDK4/6 degraders with inhibitors of parallel pathways, such as PI3K, AKT, MEK or ERK inhibitors, are likely to be most effective.
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TCI Translational Oncology Seminar Series
"Targeting the TP53 pathway to treat and prevent leukemia"
"Molecular safeguards in hematopoietic stem cells"
TCI Seminar Series
Hematology/Medical Oncology Grand Rounds
TCI Special Seminar
"Lineage plasticity in the benign and malignant prostate"
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International School of Immunotherapy 2021:
Emerging Concepts in the Design of Immunotherapy Strategies
March 22-26
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Click here for a partial list of Mount Sinai presentations.
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Voting is underway for the 2021 U.S. News & World Report “Best Hospitals” and “Best Children’s Hospitals” rankings. Voting is open through Friday, March 26.
The primary way for eligible physicians to vote is via
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Do you have news for the next issue of TCI Connections?
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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