Dana-Farber Cancer Institute News - January 15, 2023

Health and Fitness

January 17, 2023

This twice-monthly newsletter highlights the research endeavors at Dana-Farber Cancer Institute, noting recently published papers available from PubMed where Dana-Farber faculty are listed as first or senior authors. If you are a Dana-Farber faculty member and you think your paper is missing from Research News, please let us know at: [email protected]. Note that there is a two-week lag in publishing so this issue reflects papers with a PubMed publication date between December 16 through December 31.

Blood

Two to Tango! IL-13 and TGF-b Drive Myelofibrosis

Jutzi JS, Mullally A

In this issue of Blood, Melo-Cardenas et al explore the role of interleukin-13 (IL-13)/IL-4 signaling in myelofibrosis as an important pathway driving fibrotic progression through megakaryocyte expansion and increased transforming growth factor-β (TGF-β) production.

Cancer Discovery

A Ubiquitination Cascade Regulating the Integrated Stress Response and Survival in Carcinomas

Cervia LD, Shibue T, Borah AA, Gaeta B, He L, Leung L, Li N, Moyer SM, Shim BH, Dumont N, Gonzalez A, Kazachkova M, Dempster JM, Krill-Burger JM, Piccioni F, Udeshi ND, Olive ME, Carr SA, Root DE, McFarland JM, Vazquez F, Hahn WC

Systematic identification of signaling pathways required for the fitness of cancer cells will facilitate the development of new cancer therapies. We used gene essentiality measurements in 1,086 cancer cell lines to identify selective co-essentiality modules and found that a ubiquitin ligase complex composed of UBA6, BIRC6, KCMF1 and UBR4, which is required for the survival of a subset of epithelial tumors that exhibit a high degree of aneuploidy. Suppressing BIRC6 in cell lines that are dependent on this complex led to a substantial reduction in cell fitness in vitro and potent tumor regression in vivo. Mechanistically, BIRC6 suppression resulted in selective activation of the integrated stress response (ISR) by stabilization of the heme-regulated inhibitor (HRI), a direct ubiquitination target of the UBA6/BIRC6/KCMF1/UBR4 complex. These observations uncover a novel ubiquitination cascade that regulates ISR and highlight the potential of ISR activation as a new therapeutic strategy.

Journal of the National Cancer Institute

Survival in Male Breast Cancer Over the Past Three Decades

Leone JP, Freedman RA, Tolaney SM, Winer EP, Lin NU, Hassett MJ

Background: Breast cancer mortality in women has declined significantly over the past several years. In men, it is unclear whether survival has changed over time. We evaluated changes in breast cancer-specific survival (BCSS) and overall survival (OS) in male breast cancer (MaBC) over the past 3 decades.

Methods: We evaluated men diagnosed with breast cancer between 1988 and 2017, reported in the Surveillance, Epidemiology, and End Results registry. Patients were categorized into 3 groups by year of diagnosis: 1988-1997, 1998-2007 and 2008-2017. BCSS and OS were estimated by Kaplan-Meier and differences between groups were compared by log-rank test. Multivariable Cox regression evaluated the independent association of year of diagnosis with BCSS and OS. All tests were 2-sided.

Results: We included 8,481 men. Overall, BCSS at 5 years was 83.69%, 83.78% and 84.41% in groups 1988-1997, 1998-2007 and 2008-2017, respectively; P=.86. There was no significant difference in BCSS between the 3 groups within each stage of disease. Among all patients, OS at 5 years was 64.61%, 67.31% and 69.05% in groups 1988-1997, 1998-2007 and 2008-2017, respectively; P=.01. In adjusted Cox models, each additional year of diagnosis had no significant association with BCSS (hazard ratio, 1.00; 95% confidence interval: 0.99-1.01; P=.75), but there was significant improvement in OS (hazard ratio, 0.99; 95% CI: 0.98-0.99; P=.009).

Conclusion: Over the past 3 decades, there has been no significant improvement in BCSS in MaBC. Changes in OS over time are consistent with increasing life expectancy. Efforts to improve BCSS in MaBC are warranted.

Proceedings of the National Academy of Sciences of the U.S.A.

Discovery of Antibodies and Cognate Surface Targets for Ovarian Cancer by Surface Profiling

Schröfelbauer B, Kimes PK, Hauke P, Reid CE, Shao K, Hill SJ, Irizarry R, Hahn WC

Although antibodies targeting specific tumor-expressed antigens are the standard of care for some cancers, the identification of cancer-specific targets amenable to antibody binding has remained a bottleneck in development of new therapeutics. To overcome this challenge, we developed a high-throughput platform that allows for the unbiased, simultaneous discovery of antibodies and targets based on phenotypic binding profiles. Applying this platform to ovarian cancer, we identified a wide diversity of cancer targets including receptor tyrosine kinases, adhesion and migration proteins, proteases and proteins regulating angiogenesis in a single round of screening using genomics, flow cytometry, and mass spectrometry. In particular, we identified BCAM as a promising candidate for targeted therapy in high-grade serous ovarian cancers. More generally, this approach provides a rapid and flexible framework to identify cancer targets and antibodies.

Science

Epigenetic Clocks, Aging, and Cancer

Johnstone SE, Gladyshev VN, Aryee MJ, Bernstein BE

Cancer and aging are accompanied by stereotyped changes to the epigenetic landscape, including progressive loss of DNA methylation over gene-poor genomic regions. Global hypomethylation arises in cells that have undergone many divisions, likely owing to imperfect maintenance. Evidence suggests that global hypomethylation represents a “mitotic clock” that counts divisions in somatic cells and functions to restrain aging cells and limit malignant progression. Therapies that modulate the pace of methylation loss or eliminate hypomethylated cells could alleviate agingassociated diseases or cancers.

Abdominal Radiology

Lexicon for Adrenal Terms at CT and MRI: A Consensus of the Society of Abdominal Radiology Adrenal Neoplasm Disease-Focused Panel

Glazer DI, Mayo-Smith WW, Brook OR, Shinagare AB, Blake MA

Biophysical Journal

Three-Phase DNA-Origami Stepper Mechanism Based on Multi-Leg Interactions

Kilwing L, Lill P, Nathwani B, Shih WM

Blood Advances

Clinical Response to Belumosudil in Bronchiolitis Obliterans Syndrome: A Combined Analysis from 2 Prospective Trials

DeFilipp Z, Kim HT, Cutler C

Blood Advances

Patient Perspectives on Testing for Clonal Hematopoiesis of Indeterminate Potential

Sella T, Fell GG, Miller PG, Gibson CJ, Snow C, Peppercorn JM, Come SE, Frank E, Neuberg DS, Ebert BL, Partridge AH

Blood Cancer Journal

In-Depth Analysis of Alternative Splicing Landscape in Multiple Myeloma and Potential Role of Dysregulated Splicing Factors

Aktas Samur A, Fulciniti M, Derebail S, Corre J, Anderson KC, Parmigiani G, Samur MK, Munshi NC

Cancer Research

Systematic Interrogation of Tumor Cell Resistance to CAR T Cell Therapy in Pancreatic Cancer

Hagel KR, Arafeh R, Gang S, Arnoff TE, Larson RC, Doench JG, Mathewson ND, Wucherpfennig KW, Maus MV, Hahn WC

Cancers

Emerging Role of Targeted Therapy in Metastatic Pancreatic Adenocarcinoma

Huffman BM, Ellis H, Jordan AC, Freed-Pastor WA, Perez K, Rubinson DA, Sethi N, Singh H,
Surana R, Wolpin BM, Aguirre AJ, Cleary JM

Cell Reports

The ADP-Ribose Hydrolase NUDT5 is Important for DNA Repair

Qi H, Price BD

Clinical Cancer Research

Targeting MET and FGFR in Relapsed or Refractory Acute Myeloid Leukemia: Preclinical and Clinical Findings, and Signal Transduction Correlates

Chen EC, Gandler H, Tosic I, Fell GG, Pozdnyakova O, DeAngelo DJ, Galinsky I, Luskin MR, Wadleigh MS, Winer ES, Leonard R, de Jonge A, Neuberg D, Look AT, Stone RM, Garcia JS

International Journal of Cancer

Dysfunctions of Innate and Adaptive Immune Tumor Microenvironment in Waldenström Macroglobulinemia

Hunter ZR, Hideshima T, Flores L, Treon SP, Dorfman DM, Anderson KC, Jakubikova J

JCO Oncology Practice

Training Hematologists/Oncologists for the Academic-Community Hybrid: Creating a Fellowship Framework for the Future

Roberts DA, Faig J, Wischhusen J, Giordano S, Acharya U, Drews R, Dougherty D, Lathan C, Rangachari D

Leukemia Research

Intensity of Induction Regimen and Outcomes Among Adults with Ph+ALL Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

Raman HS, Kim SE, DeAngelo DJ, Stevenson KE, Neuberg D, Winer ES, Wadleigh M, Garcia JS,
Kim AS, Stone RM, Ho VT, Luskin MR

Nature Nanotechnology

Multi-Micron Crisscross Structures Grown from DNA-Origami Slats

Wintersinger CM, Minev D, Ershova A, Sasaki HM, Gowri G, Berengut JF, Corea-Dilbert FE, Yin P, Shih WM