Welcome to Dana-Farber's Research News
April 15, 2022
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.
Blood
Overcoming IMiD Resistance in T-Cell Lymphomas Through Potent Degradation of ZFP91 and IKZF1
Wu W, Nelson GM, Donovan KA, Nowak RP, Heavican-Foral TB, Nirmal AJ, Liu H, Yang L, Duffy J, Powers F, Stevenson KE, Jones MK, Ng SY, Wu G, Jain S, Xu R, Amaka S, Trevisani C, Donaldson NL, Fischer ES, Adelman K, Weinstock DM
Immunomodulatory (IMiD) agents like lenalidomide and pomalidomide induce the recruitment of IKZF1 and other targets to the CRL4CRBN E3 ubiquitin ligase, resulting in their ubiquitination and degradation. These agents are highly active in B-cell lymphomas and a subset of myeloid diseases but have compromised effects in T-cell lymphomas (TCLs). Here, we show that 2 factors determine resistance to IMiDs among TCLs. First, limited CRBN expression reduces IMiD activity in TCLs but can be overcome by newer-generation degrader CC-92480. Using mass spectrometry, we show that CC-92480 selectively degrades IKZF1 and ZFP91 in TCL cells with greater potency than pomalidomide. As a result, CC-92480 is highly active against multiple TCL subtypes and showed greater efficacy than pomalidomide across 4 in vivo TCL models. Second, we demonstrate that ZFP91 functions as a bona fide transcription factor that coregulates cell survival with IKZF1 in IMiD-resistant TCLs. By activating keynote genes from WNT, NF-kB, and MAP kinase signaling, ZFP91 directly promotes resistance to IKZF1 loss. Moreover, lenalidomide-sensitive TCLs can acquire stable resistance via ZFP91 rewiring, which involves casein kinase 2-mediated c-Jun inactivation. Overall, these findings identify a critical transcription factor network within TCLs and provide clinical proof of concept for the novel therapy using next-generation degraders.
Gastroenterology
DETECT: DEvelopment of Technologies for Early HCC DeTection
Tayob N
Hepatocellular carcinoma (HCC) is a leading cause of morbidity and mortality in patients with cirrhosis and the 3rd most common cause of cancer-related deaths worldwide. Though considered a highly fatal cancer with 5-year survival <15%, curative treatments (i.e., surgical resection, liver transplantation, ablation) are available for patients diagnosed at an early stage. U.S. professional society guidelines recommend HCC surveillance in patients with cirrhosis of any etiology using biannual ultrasound serum alpha-fetoprotein (AFP), which is associated with survival benefits and curative treatment receipt. However, ultrasound AFP can be associated with physical harms, i.e., the need for multiple contrast-enhanced cross-sectional imaging studies and biopsies, driven by false-positive tests or indeterminate lesions. Moreover, several new challenges in HCC surveillance are emerging. Contemporary Western cirrhosis cohorts consist of a higher proportion of patients with hepatitis C virus (HCV) post-sustained virologic response and non-alcoholic fatty liver disease (NAFLD) with a lower annual risk of HCC (1-3%), compared to older cohorts with viremic HCV (3-8%). However, given the high prevalence of NAFLD in the U.S., the at-risk population is growing. Given cost and capacity concerns, screening all patients with NAFLD is not feasible. Similar challenges exist for patients with HCV-related cirrhosis who have been cured. In addition, ultrasound has several limitations, including operator dependence and limited visualization in selected patients (particularly in the setting of abdominal adiposity and hepatic steatosis) and low sensitivity for early HCC (~45%). Further, given logistical barriers imaging-based surveillance continues to be underutilized in clinical practice, with utilization rates of only 24%.5 Thus, the current “one-size-fits-all” model of ultrasound-based surveillance should be challenged and the discovery of new approaches and biomarkers are warranted.
Journal of Clinical Oncology
Apoptosis: Directly Targeted at Last
Letai A
Every cell in our bodies is encoded with pathways of programmed cell death so that useless or harmful cells can be eliminated for the benefit of the organism as a whole. Among these, the mitochondrial pathway of apoptosis is prominent for its role in oncogenesis and response to cancer therapy. The selective activation of apoptosis in cancer cells has been an important goal in oncology for decades. Recently, a class of drugs called BH3 mimetics has emerged. In the original report that accompanies this article, Harrison et al present another novel application of BH3 mimetic therapy with navitoclax in the context of myelofibrosis.
The Lancet Oncology
Immune checkpoint inhibitors and timing of administration
Duma N
We read with immense interest the Article by David C Qian and colleagues in The Lancet Oncology. The study reported impairments in overall survival in patients who received more than 20% of immune checkpoint blockade infusions after 1630 h. However, the socioeconomic and demographic characteristics of the patients were not mentioned. This is particularly important in this study, as both the primary predictor (ie, infusion time) and the clinical outcome (ie, overall survival) tested bear great potential to be affected by social factors. Notably, in the study by Long and colleagues, which was cited several times by Qian and colleagues and suggested enhanced antibody response with morning vaccination, the sociodemographic factors were examined in detail.
Molecular Cell
Olsen SN, Godfrey L, Healy JP, Choi YA, Kai Y, Hatton C, Perner F, Haarer EL, Armstrong SA
MLL rearrangements produce fusion oncoproteins that drive leukemia development, but the direct effects of MLL-fusion inactivation remain poorly defined. We designed models with degradable MLL::AF9 where treatment with small molecules induces rapid degradation. We leveraged the kinetics of this system to identify a core subset of MLL::AF9 target genes where MLL::AF9 degradation induces changes in transcriptional elongation within 15 minutes. MLL::AF9 degradation subsequently causes loss of a transcriptionally active chromatin landscape. We used this insight to assess the effectiveness of small molecules that target members of the MLL::AF9 multiprotein complex, specifically DOT1L and MENIN. Combined DOT1L/MENIN inhibition resembles MLL::AF9 degradation, whereas single-agent treatment has more modest effects on MLL::AF9 occupancy and gene expression. Our data show that MLL::AF9 degradation leads to decreases in transcriptional elongation prior to changes in chromatin landscape at select loci and that combined inhibition of chromatin complexes releases the MLL::AF9 oncoprotein from chromatin globally.
Nature Biotechnology
Haplotype-Resolved Assembly of Diploid Genomes Without Parental Data
Cheng H, Li H
Routine haplotype-resolved genome assembly from single samples remains an unresolved problem. Here we describe an algorithm that combines PacBio HiFi reads and Hi-C chromatin interaction data to produce a haplotype-resolved assembly without the sequencing of parents. Applied to human and other vertebrate samples, our algorithm consistently outperforms existing single-sample assembly pipelines and generates assemblies of similar quality to the best pedigree-based assemblies.
Nature Communications
Ni J, Kabraji S, Xie S, Wang Y, Pan P, He X, Liu Z, Leone JP, Long HW, Brown MA, Winer EP, Dillon DAR, Lin NU, Zhao JJ
Approximately 50% of patients with metastatic HER2-positive (HER2+) breast cancer develop brain metastases (BCBMs). We report that the tumor suppressor p16INK4A is deficient in the majority of HER2+BCBMs. p16INK4A-deficiency as measured by protein immunohistochemistry predicted response to combined tucatinib and abemaciclib in orthotopic patient-derived xenografts (PDXs) of HER2+BCBMs. Our findings establish the rationale for a biomarker-driven clinical trial of combined CDK4/6- and HER2-targeted agents for patients with HER2+BCBM.
Science
Copper Induces Cell Death by Targeting Lipoylated TCA Cycle Proteins
Tsvetkov P, Coy S, Petrova B, Dreishpoon M, Verma A, Abdusamad M, Rossen J, Joesch-Cohen L, Humeidi R, Spangler RD, Eaton JK, Kocak M, Corsello SM, Kanarek N, Santagata S, Golub TR
Copper is an essential cofactor for all organisms, and yet it becomes toxic if concentrations exceed a threshold maintained by evolutionarily conserved homeostatic mechanisms. How excess copper induces cell death, however, is unknown. Here, we show in human cells that copper-dependent, regulated cell death is distinct from known death mechanisms and is dependent on mitochondrial respiration. We show that copper-dependent death occurs by means of direct binding of copper to lipoylated components of the tricarboxylic acid (TCA) cycle. This results in lipoylated protein aggregation and subsequent iron-sulfur cluster protein loss, which leads to proteotoxic stress and ultimately cell death. These findings may explain the need for ancient copper homeostatic mechanisms.
Blood Cancer Journal
Extramedullary Disease in Multiple Myeloma: A Systematic Literature Review
Richardson P
British Journal of Haematology
Valtis YK, Place AE, Silverman LB, Vrooman LM, DeAngelo DJ, Luskin MR
Brachytherapy
Kaza E, Lee CY, King MT, Dyer MA, Cormack RA, Buzurovic I
Cell Chemical Biology
Vander Heiden MG
Clinical Cancer Research
Hemming ML, Bhola P, Loycano MA, Anderson JA, Taddei ML, Doyle LA, Lavrova E, Andersen JL, Klega KS, Benson MR, Crompton BD, Raut CP, George S, Letai A, Demetri GD, Sicinska E
Developmental Cell
YAP-deLIVERing the Directions and the Fuel
Freeburg SH, Goessling W
European Journal of Cancer
Gelber RD, Wang XV, Krop I, Frank E
Head and Neck
Arbab M, Chen YH, Tishler RB, Gunasti L, Glass J, Fugazzotto JA, Killoran JH, Sethi R, Rettig E, Annino D, Goguen L, Uppaluri R, Hsu C, Burke E, Hanna GJ, Haddad RI, Margalit DN, Schoenfeld JD
Journal of the American Society of Nephrology
Gelfand SL
Journal of Clinical Investigation
Shapiro RM, Birch GC, Vergara Cadavid J, Nikiforow S, Baginska J, Ali AK, Tarannum M, Sheffer M, Abdulhamid YZ, Rambaldi B, Arihara Y, Reynolds C, Halpern MS, Rodig SJ, Cullen N, Wolff JO, Pfaff KL, Lane AA, Lindsley RC, Cutler CS, Antin JH, Ho VT, Koreth J, Gooptu M, Kim HT, Wu CJ, Soiffer RJ, Ritz J, Romee R
Journal of Molecular Biology
Eukaryotic Initiation Factor 5A2 Regulates Expression of Antiviral Genes
Farache D, Liu L, Lee ASY
Journal of Pain and Symptom Management
Identification of Distinct Symptom Profiles in Cancer Patients Using a Pre-Specified Symptom Cluster
Hammer MJ
Journal of Palliative Medicine
Pozzar RA, Enzinger AC, Poort H, Furey A, Orechia M, Thompson E, Tavormina A, Fenton ATHR, Jaung T, Braun IM, DeMarsh A, Cooley ME, Wright AA
Journal of Thoracic Oncology
Concurrent TP53 Mutations Facilitate Resistance Evolution in EGFR Mutant Lung Adenocarcinoma
Chambers E, Nguyen T, Coolidge A, Lydon CA, Sholl L, Nishino M, Van Allen EM, Jänne PA
Journal of Virology
Nguyen HT, Qualizza A, Anang S, Zhao M, Zou S, Zhou R, Wang Q, Zhang S, Sodroski JG
Lancet Haematology
El-Khoury H, Lee DJ, Alberge JB, Redd R, Cea-Curry CJ, Perry J, Barr H, Murphy C, Leblebjian H, Davis MI, Amstutz J, Boehner CJ, Lightbody ED, Sklavenitis-Pistofidis R, Mo CC, Weiss ST, Karlson E, Trippa L, Rebbeck TR, Getz G, Marinac CR, Ghobrial IM
Molecular Therapy - Oncolytics
Anti-CAIX BBz CAR4/8 T-Cells Exhibit Superior Efficacy in a ccRCC Mouse Model
Wang Y, Buck A, Grimaud M, Culhane AC, Kodangattil S, Razimbaud C, Bonal DM, Nguyen QD, Zhu Z, Wei K, O'Donnell ML, Huang Y, Signoretti S, Choueiri TK, Freeman GJ, Zhu Q, Marasco WA
Nature Reviews Cancer
Targeting CDK4 and CDK6 in Cancer
Bergholz JS, Zhao JJ
Oncologist
Ravi P, Ravi A, Riaz IB, Freeman D, Curran C, Mantia C, McGregor BA, Kilbridge KL, Pan CX, Sonpavde GP
Oncologist
Qin L, Bakouny Z, Krajewski KM, Van Allen EM, Choueiri TK, Shinagare AB
Pediatric Blood and Cancer
Flamand Y, Blonquist T, Stevenson KE, Harris MH, Neuberg DS, Sallan SE, Silverman LB
Proceedings of the National Academy of Science of the U.S.A
Sensitivity of VHL Mutant Kidney Cancers to HIF2 Inhibitors Does Not Require an Intact p53 Pathway
Stransky LA, Vigeant SM, Huang B, West D, Denize T, Walton E, Signoretti S, Kaelin WG Jr
STAR Protocols
Mass Cytometry Staining for Human Bone Marrow Clinical Samples
Hallisey M, Dennis J, Abrecht C, Pistofidis RS, Schork AN, Lightbody ED, Heilpern-Mallory D, Severgnini M, Ghobrial IM, Hodi FS, Baginska J