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.
Clonal Hematopoiesis Transcending Species Barriers
Rauch PJ, Ebert BL
In this issue of Blood, Shin et al expand our understanding of clonal hematopoiesis (CH) by showing its natural emergence in aged non-human primates (rhesus macaques), and by demonstrating robust expansion of TET2-mutated clones causing hyperinflammation in a CRISPR-Cas9–based autologous transplantation model in macaques.
Lenalidomide Promotes the Development of TP53-Mutated Therapy-Related Myeloid Neoplasms
Sperling AS, Kennedy JA, Nguyen AT, Miller PG, McConkey ME, Quevedo Barrios VA, Ebert BL
There is a growing body of evidence that therapy-related myeloid neoplasms (t-MNs) with driver gene mutations arise in the background of clonal hematopoiesis (CH) under the positive selective pressure of chemo- and radiation therapies. Uncovering the exposure relationships that provide selective advantage to specific CH mutations is critical to understanding the pathogenesis and etiology of t-MNs. In a systematic analysis of 416¬†patients with t-MN and detailed prior exposure history, we found that TP53 mutations were significantly associated with prior treatment with thalidomide analogs, specifically lenalidomide. We demonstrated experimentally that lenalidomide treatment provides a selective advantage to Trp53-mutant hematopoietic stem and progenitor cells (HSPCs) in¬†vitro and in¬†vivo, the effect of which was specific to Trp53-mutant HSPCs and was not observed in HSPCs with other CH mutations. Because of the differences in CK1Œ± degradation, pomalidomide treatment did not provide an equivalent level of selective advantage to Trp53-mutant HSPCs, providing a biological rationale for its use in patients at high risk for t-MN. These findings highlight the role of lenalidomide treatment in promoting TP53-mutated t-MNs and offer a potential alternative strategy to mitigate the risk of t-MN development.
BAF Complex Maintains Glioma Stem Cells in Pediatric H3K27M-Glioma
Panditharatna E, Wang T, Trissal MC, Liu I, Jiang L, Li D, Hoffman SE, Kugener G, Shaw ML, Mire HM, Hack OA, Dempster JM, Dai L, Sigua LH, Wyatt M, Kalani Z, Goodale A, Vazquez F, Piccioni F, Doench JG, Root DE, Anastas JN, Jones KL, Saur Conway A, Stopka S, Regan MS, Liang Y, Seo HS, Song K, Bashyal P, Jerome WP, Mathewson ND, Dhe-Paganon S, Suva ML, Nguyen QD, Ligon KL, Shi Y, Agar NYR, Stegmaier K, Stiles CD, Golub TR, Qi J, Filbin MG
Diffuse midline gliomas are uniformly fatal pediatric central nervous system cancers, refractory to standard of care therapeutic modalities. The primary genetic drivers are a set of recurrent amino acid substitutions in genes encoding histone H3 (H3K27M), which are currently undruggable. These H3K27M oncohistones perturb normal chromatin architecture, resulting in an aberrant epigenetic landscape. To interrogate for epigenetic dependencies, we performed a CRISPR screen and show that patient-derived H3K27M-glioma neurospheres are dependent on core components of the mammalian BAF (SWI/SNF) chromatin remodeling complex. The BAF complex maintains glioma stem cells in a cycling, oligodendrocyte precursor cell (OPC)-like state, where genetic perturbation of the BAF catalytic subunit SMARCA4 (BRG1), as well as pharmacological suppression opposes proliferation, promotes progression of differentiation along the astrocytic lineage, and improves overall survival of patient-derived xenograft models. In summary, we demonstrate that therapeutic inhibition of BAF complex has translational potential for children with H3K27M-gliomas.
Osimertinib+Savolitinib to Overcome Acquired MET-Mediated Resistance in Epidermal Growth Factor Receptor Mutated MET-Amplified Non-Small Cell Lung Cancer: TATTON
Sequist LV, Janne PA
MET-inhibitor and epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) combination therapy could overcome acquired MET-mediated osimertinib resistance. We present the final PhIb TATTON (NCT02143466) analysis (Part B, n=138/Part D, n=42) assessing oral savolitinib 600 mg/300 mg once daily (QD) + osimertinib 80 mg QD in patients with MET amplified EGFR mutated (EGFRm) advanced non-small cell lung cancer (NSCLC) and progression on prior EGFR-TKI. An acceptable safety profile was observed. In Parts B and D, respectively, objective response rates were 33-67% and 62%, and median progression-free survival (PFS) was 5.5-11.1 and 9.0 months. Increased antitumor activity may occur with MET copy-number 10. EGFRm circulating tumor DNA clearance on treatment predicted longer PFS in patients with detectable baseline ctDNA, while acquired resistance mechanisms to osimertinib+savolitinib were mediated by MET, EGFR, or KRAS alterations.
Covalent Disruptor of YAP-TEAD Association Suppresses Defective Hippo Signaling
Fan M, Che J, Kwiatkowski NP, Gao Y, Seo HS, Ficarro SB, Gokhale PC, Liu Y, Geffken EA, Lakhani J, Song K, Kuljanin M, Ji W, Jiang J, He Z, Boghossian AS, Rees MG, Ronan MM, Roth JA, Mancias JD, Marto JA, Dhe-Paganon S
The transcription factor TEAD, together with its coactivator YAP/TAZ, is a key transcriptional modulator of the Hippo pathway. Activation of TEAD transcription by YAP has been implicated in a number of malignancies, and this complex represents a promising target for drug discovery. However, both YAP and its extensive binding interfaces to TEAD have been difficult to address using small molecules, mainly due to a lack of druggable pockets. TEAD is post-translationally modified by palmitoylation that targets a conserved cysteine at a central pocket, which provides an opportunity to develop cysteine-directed covalent small molecules for TEAD inhibition. Here, we employed covalent fragment screening approach followed by structure-based design to develop an irreversible TEAD inhibitor MYF-03-69. Using a range of in vitro and cell-based assays we demonstrated that through a covalent binding with TEAD palmitate pocket, MYF-03-69 disrupts YAP-TEAD association, suppresses TEAD transcriptional activity and inhibits cell growth of Hippo signaling defective malignant pleural mesothelioma (MPM). Further, a cell viability screening with a panel of 903 cancer cell lines indicated a high correlation between TEAD-YAP dependency and the sensitivity to MYF-03-69. Transcription profiling identified the upregulation of proapoptotic BMF gene in cancer cells that are sensitive to TEAD inhibition. Further optimization of MYF-03-69 led to an in vivo compatible compound MYF-03-176, which shows strong antitumor efficacy in MPM mouse xenograft model via oral administration. Taken together, we disclosed a story of the development of covalent TEAD inhibitors and its high therapeutic potential for clinic treatment for the cancers that are driven by TEAD-YAP alteration.
Journal of Clinical Oncology
Positron Emission Tomography-Adapted Therapy in Bulky Stage I/II Classic Hodgkin Lymphoma: CALGB 50801 (Alliance)
LaCasce AS, Abramson J
PURPOSE:Patients with bulky stage I/II classic Hodgkin lymphoma (cHL) are typically treated with chemotherapy followed by radiation. Late effects associated with radiotherapy include increased risk of second cancer and cardiovascular disease. We tested a positron emission tomography (PET)-adapted approach in patients with bulky, early-stage cHL, omitting radiotherapy in patients with interim PET-negative (PET-) disease and intensifying treatment in patients with PET-positive (PET+) disease.
METHODS:Eligible patients with bulky disease (mass > 10 cm or 1/3 the maximum intrathoracic diameter on chest x-ray) received two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by interim fluorodeoxyglucose PET (PET2). Patients with PET2-, defined as 1-3 on the 5-point scale, received four additional cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine. Patients with PET2+ received four cycles of escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone followed by 30.6 Gy involved-field radiation.
RESULTS:Of 94 evaluable patients, 53% were female with median age 30 years (range, 18-58 years). Eight-five (90%) had stage II disease, including 48 (51%) with stage IIB/IIBE. Seventy-eight (78%) were PET2- and 21 (22%) were PET2+. The predominant toxicity was neutropenia, with 9% of patients developing febrile neutropenia and one developing sepsis. The primary end point of 3-year progression-free survival (PFS) was 93.1% in PET2- and 89.7% in PET2+ patients. Three-year overall survival was 98.6% and 94.4%, respectively. The estimated hazard ratio comparing PFS of patients with PET2+ and patients with PET2- was 1.03 (85% upper bound 2.38) and was significantly less than the null hypothesis of 4.1 (one-sided P = .04).
CONCLUSION:Our study of PET-adapted therapy in bulky stage I/II cHL met its primary goal and was associated with an excellent 3-year PFS rate of 92.3% in all patients, with the majority being spared radiotherapy and exposure to intensified chemotherapy.
Journal of Clinical Oncology
Rare Germline ATM Variants Influence the Development of Chronic Lymphocytic Leukemia
Lampson BL, Gupta A, Tyekucheva S, Mashima K, Wang Z, Wojciechowska N, Shaughnessy CJ, Baker PO, Fernandes SM, Shupe S, Machado JH, Fardoun R, Kim AS, Brown JR
PURPOSE:Germline missense variants of unknown significance in cancer-related genes are increasingly being identified with the expanding use of next-generation sequencing. The ataxia telangiectasia-mutated (ATM) gene on chromosome 11 has more than 1,000 germline missense variants of unknown significance and is a tumor suppressor. We aimed to determine if rare germline ATM variants are more frequent in chronic lymphocytic leukemia (CLL) compared with other hematologic malignancies and if they influence the clinical characteristics of CLL.
METHODS:We identified 3,128 patients (including 825 patients with CLL) in our hematologic malignancy clinic who had received clinical-grade sequencing of the entire coding region of ATM. We ascertained the comparative frequencies of germline ATM variants in categories of hematologic neoplasms, and, in patients with CLL, we determined whether these variants affected CLL-associated characteristics such as somatic 11q deletion.
RESULTS:Rare germline ATM variants are present in 24% of patients with CLL, significantly greater than that in patients with other lymphoid malignancies (16% prevalence), myeloid disease (15%), or no hematologic neoplasm (14%). Patients with CLL with germline ATM variants are younger at diagnosis and twice as likely to have 11q deletion. The ATM variant p.L2307F is present in 3% of patients with CLL, is associated with a three-fold increase in rates of somatic 11q deletion, and is a hypomorph in cell-based assays.
CONCLUSION:Germline ATM variants cluster within CLL and affect the phenotype of CLL that develops, implying that some of these variants (such as ATM p.L2307F) have functional significance and should not be ignored. Further studies are needed to determine whether these variants affect the response to therapy or account for some of the inherited risk of CLL.
Nature Chemical Biology
Velcrin-Induced Selective Cleavage of tRNA(Leu)(TAA) by SLFN12 Causes Cancer Cell Death
Lee S, Hoyt S, Wu X, Garvie C, McGaunn J, Shekhar M, Tötzl M, Rees MG, Cherniack AD, Meyerson M, Greulich H
Velcrin compounds kill cancer cells expressing high levels of phosphodiesterase 3A (PDE3A) and Schlafen family member 12 (SLFN12) by inducing complex formation between these two proteins, but the mechanism of cancer cell killing by the PDE3A-SLFN12 complex is not fully understood. Here, we report that the physiological substrate of SLFN12 RNase is tRNALeu(TAA). SLFN12 selectively digests tRNALeu(TAA), and velcrin treatment promotes the cleavage of tRNALeu(TAA) by inducing PDE3A-SLFN12 complex formation in vitro. We found that distinct sequences in the variable loop and acceptor stem of tRNALeu(TAA) are required for substrate digestion. Velcrin treatment of sensitive cells results in downregulation of tRNALeu(TAA), ribosome pausing at Leu-TTA codons and global inhibition of protein synthesis. Velcrin-induced cleavage of tRNALeu(TAA) by SLFN12 and the concomitant global inhibition of protein synthesis thus define a new mechanism of apoptosis initiation.
American Journal of Hematology
Molecular Predictors of Immunophenotypic Measurable Residual Disease Clearance in Acute Myeloid Leukemia
Annals of Internal Medicine
Environmental Health: Translating Policy Into Action
An Agenda to Advance Research in MDS: A TOP 10 Priority List from the First International Workshop in MDS (iwMDS)
Stahl M, Kuchroo V, Hasserjian RP, Brunner AM
A Distinct Chromatin State Drives Therapeutic Resistance in Invasive Lobular Breast Cancer
Nardone A, Qiu X, Spisak S, Nagy Z, Feiglin A, Feit A, Cohen Feit G, Xie Y, Font-Tello A, Guarducci C, Hermida-Prado F, Syamala S, Lim K, Munoz Gomez M, Pun M, Cornwell M, Liu W, Cejas P, Brock JB, Freedman ML, Winer EP, Long HW, Metzger Filho O, Jeselsohn R
Targeting DNA Repair with Combined Inhibition of NHEJ and MMEJ Induces Synthetic Lethality in TP53-Mutant Cancers
Patterson-Fortin J, Bose A, Tsai WC, Grochala C, Nguyen H, Zhou J, Parmar K, Lazaro JB, Liu J, McQueen K, Shapiro GI, Kozono D, D'Andrea AD
Fusobacterium and Colorectal Cancer: Important Association or Random Coincidence?
Sanders BE, Qiao G, Hirschman J, Meyerson M
The Dawn of the Antibody-Drug Conjugates Era: How T-DM1 Reinvented the Future of Chemotherapy for Solid Tumors
Tarantino P, Tolaney SM
Cell Chemical Biology
Exploring the Target Scope of KEAP1 E3 Ligase-Based PROTACs
Du G, Jiang J, Henning NJ, Safaee N, Koide E, Nowak RP, Donovan KA, Yoon H, You I, Yue H, Eleuteri NA, He Z, Huang HT, Che J, Fischer ES
Coming of Age for BTK Inhibitor Therapy: A Review of Zanubrutinib in Waldenström Macroglobulinemia
Sarosiek S, Castillo JJ
Upfront Cytoreductive Nephrectomy for Metastatic Renal Cell Carcinoma Treated with Immune Checkpoint Inhibitors or Targeted Therapy: An Observational Study from the International Metastatic Renal Cell Carcinoma Database Consortium
Bakouny Z, El Zarif T, Ravi P, Steinharter JA, Xie W, Choueiri TK
Expert Review of Anticancer Therapy
Lutetium Lu 177 Vipivotide Tetraxetan for Metastatic Castration-Resistant Prostate Cancer
Shah H, Ravi P, Sonpavde G, Jacene H
International Journal of Molecular Sciences
Advances in the Management of Central Nervous System Metastases from Breast Cancer
Journal of Applied Clinical Medical Physics
Image Quality Comparisons of Coil Setups in 3T MRI for Brain and Head and Neck Radiotherapy Simulations
Kaza E, Guenette JP, Guthier CV, Hatch S, Marques A, Singer L, Schoenfeld JD
Journal of Pain and Symptom Management
Communication Training and Code Status Conversation Patterns Reported by Emergency Clinicians
Prachanukool T, Aaronson EL, Lakin JR, Higuchi M, Lee RS, Santangelo I, Hasdianda MA, Wang W, Liu SW, Kennedy M, Schonberg MA, Block SD, Tulsky JA, Ouchi K
JAMA Otolaryngology-Head and Neck Surgery
Association of Pretreatment Circulating Tumor Tissue-Modified Viral HPV DNA With Clinicopathologic Factors in HPV-Positive Oropharyngeal Cancer
Rettig EM, Wang AA, Tran NA, Carey E, Dey T, Schoenfeld JD, Sehgal K, Guenette JP, Margalit DN, Sethi R, Uppaluri R, Tishler RB, Annino DJ, Goguen LA, Jo VY, Haddad RI, Hanna GJ
Leukemia and Lymphoma
Venetoclax-Based Salvage Therapy in Patients with Relapsed/Refractory Acute Myeloid Leukemia Previously Treated with FLT3 or IDH1/2 Inhibitors
Shimony S, DeAngelo DJ, Stone RM, Stahl M
Negative Trials Over and Over Again: How Can We Do Better?
McFaline-Figueroa JR, Wen PY
A Systematic Review of Patient Education Strategies for Oncology Patients in Low- and Middle-Income Countries
Buswell L, Fadelu T
End-of-Life Care and Advanced Directives in Hispanic/Latinx Patients: Challenges and Solutions for the Practicing Oncologist
Pediatric Blood and Cancer
Transient Neonatal Hemolytic Anemia Due to the Novel Gamma Globin Gene Mutation HBG2:C.290T>C, p.Leu97Pro (Hemoglobin Wareham)
Gorfinkel L, Wachter F, Hansbury E, Williams DA, Chui DHK, Cantor AB
Pediatric Blood and Cancer
"The Simple Life Experiences that Every Other Human Gets": Desire for Normalcy Among Adolescents and Young Adults with Advanced Cancer
Umaretiya PJ, Fisher L, Vega B, Rodrigues G, Fasciano KM, Lakin JR, Lefebvre A, Wall CB, Bona K, Mack JW
What Bacterial Cell Death Teaches Us About Life
Johnson AG, Kranzusch PJ
Molecular Characterization and Therapeutic Approaches to Small Cell Lung Cancer: Imaging Implications
Park H, Tseng SC, Sholl LM, Hatabu H, Awad MM, Nishino M
Seminars in Respiratory and Critical Care Medicine
Imaging of Drug-Related Pneumonitis in Oncology
Tseng SC, Nishino M