Welcome to Dana-Farber's Research News
March 15, 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: Michael_buller@dfci.harvard.edu.
Cancer Discovery
Addressing Tumor Heterogeneity by Sensitizing Resistant Cancer Cells to T Cell-Secreted Cytokines
Zhang X, Juan TY, Pyrdol JW, Kyrysyuk O, Doench JG, Liu XS, Wucherpfennig KW
Tumor heterogeneity is a major barrier to cancer therapy, including immunotherapy. Activated T cells can efficiently kill tumor cells following recognition of MHC class I (MHC-I) bound peptides, but this selection pressure favors outgrowth of MHC-I deficient tumor cells. We performed a genome-scale screen to discover alternative pathways for T cell-mediated killing of MHC-I deficient tumor cells. Autophagy and TNF signaling emerged as top pathways, and inactivation of Rnf31 (TNF signaling) and Atg5 (autophagy) sensitized MHC-I deficient tumor cells to apoptosis by T cell-derived cytokines. Mechanistic studies demonstrated that inhibition of autophagy amplified pro-apoptotic effects of cytokines in tumor cells. Antigens from apoptotic MHC-I deficient tumor cells were efficiently cross-presented by dendritic cells, resulting in heightened tumor infiltration by IFNa and TNFg-producing T cells. Tumors with a substantial population of MHC-I deficient cancer cells could be controlled by T cells when both pathways were targeted using genetic or pharmacological approaches.
Cancer Discovery
Gunn K, Huang B, Rouaisnel B, Doench JG, Ligon KL, Losman JA
Oncogenic mutations in isocitrate dehydrogenase (IDH)-1 and -2 occur in a wide range of cancers, including acute myeloid leukemia (AML) and glioma. Mutant IDH enzymes convert 2-oxoglutarate (2OG) to (R)-2-hydroxyglutarate ((R)-2HG)), an oncometabolite that is hypothesized to promote cellular transformation by dysregulating 2OG-dependent enzymes. The only (R)-2HG target that has been convincingly shown to contribute to transformation by mutant IDH is the myeloid tumor suppressor TET2. However, there is ample evidence to suggest that (R)-2HG has other functionally relevant targets in IDH-mutant cancers. Here, we show that (R)-2HG inhibits KDM5 histone lysine demethylases and that this inhibition contributes to cellular transformation in IDH-mutant AML and IDH-mutant glioma. These studies provide the first evidence of a functional link between dysregulation of histone lysine methylation and transformation in IDH-mutant cancers.
Nature Chemical Biology
Depletion of Creatine Phosphagen Energetics with a Covalent Creatine Kinase Inhibitor
Darabedian N, Lin S, Seo HS, Mills EL, Xiao H, Johnson JL, Che J, Cantley LC, Dhe-Paganon S, Stegmaier K, Chouchani ET
Creatine kinases (CKs) provide local ATP production in periods of elevated energetic demand, such as during rapid anabolism and growth. Thus, creatine energetics has emerged as a major metabolic liability in many rapidly proliferating cancers. Whether CKs can be targeted therapeutically is unknown because no potent or selective CK inhibitors have been developed. Here we leverage an active site cysteine present in all CK isoforms to develop a selective covalent inhibitor of creatine phosphagen energetics, CKi. Using deep chemoproteomics, we discover that CKi selectively engages the active site cysteine of CKs in cells. A co-crystal structure of CKi with creatine kinase B indicates active site inhibition that prevents bidirectional phosphotransfer. In cells, CKi and its analogs rapidly and selectively deplete creatine phosphate, and drive toxicity selectively in CK-dependent acute myeloid leukemia. Finally, we use CKi to uncover an essential role for CKs in the regulation of proinflammatory cytokine production in macrophages.
New England Journal of Medicine
Overcoming Resistance - Omission of Radiotherapy for Low-Risk Breast Cancer
Bellon JR
In this issue of the Journal, Kunkler and colleagues report the highly anticipated 10-year results of the PRIME II trial, which show that omission of radiotherapy did not affect survival after breast-conserving surgery in women 65 years of age or older with T1 or T2 (tumors ?3 cm in the largest dimension), node-negative, estrogen receptor (ER)–positive breast cancer. These data offer a response to the long-standing problem of overtreatment in older women with low-risk breast cancer. The ability to omit radiotherapy is one of many options in a lengthy list that also includes the use of abbreviated radiotherapy regimens and smaller target volumes. It is indisputable that omitting radiotherapy can allow the patient to avoid side effects such as breast pain, dermatitis, and the risk of heart and lung complications. Pragmatically, radiotherapy can strain time and finances. Therefore, robust data solidifying the option to omit radiotherapy in selected patients are welcome.
Biostatistics
Wu X, Dominici F, Braun D
Blood Advances
Peripheral Blood Monocyte Count is a Dynamic Prognostic Biomarker in Multiple Myeloma
Hassan H, Fillmore NR, Munshi NC
European Urology Oncology
McGregor B, Choueiri TK
Frontiers in Immunology
Lin Z, Wang Q, Jiang T, Wang W, Zhao JJ
Journal of the American College of Radiology
Frequency and Clinical Utility of Alerts for Intra-Institutional Radiologist Discrepant Opinions
DiPiro PJ, Licaros A, Zhao AH, Glazer DI, Healey MJ, Curley PJ, Giess CS, Khorasani R
Journal of General Internal Medicine
Barriers Patients Face in Predicting Cost of Care Despite Increasing Healthcare Price Transparency
Milosavljevic S, Milligan MG, Lam MB
Journal of Virology
Nguyen HT, Wang Q, Anang S, Sodroski JG
JCO Oncology Practice
The Day One Talk, 20 Years Later: What Have We Learned?
Mack JW
Oncologist
Perez K, Cleary JM, Horick N, Weekes C, Abrams T, Blaszkowsky L, Enzinger P, Giannakis M,
Goyal L, Meyerhardt JA, Rubinson D, Yurgelun MB, Goessling W, Giantonio BJ, Brais L, Germon V, Stonely D, Raghavan S, Aguirre AJ, Wolpin BM
