Welcome to Dana-Farber's Research News
July 15, 2024
This twice-monthly newsletter highlights recently published research where Dana-Farber faculty are listed as first or senior authors. The information is pulled from PubMed and this issue notes papers published from June 16 through June 30.
If you are a Dana-Farber faculty member and you think your paper is missing from Research News, please let us know by emailing ericd_schuller@dfci.harvard.edu.
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Blood
Loss of GABARAP Mediates Resistance to Immunogenic Chemotherapy in Multiple Myeloma
Johnstone M, Samur MK, Cifric S, Folino P, Vinaixa D, Clericuzio C, Favasuli VK, Maisano D, Talluri S, Prabhala R, Bianchi G, Fulciniti M, Wen K, Kurata K, Liu J, Penailillo J, Richardson PG, Chauhan D, Carrasco RD, Hideshima T, Munshi NC, Anderson KC
Immunogenic cell death (ICD) is a form of cell death by which cancer treatments can induce a clinically relevant antitumor immune response in a broad range of cancers. In multiple myeloma (MM), the proteasome inhibitor bortezomib is an ICD inducer and creates durable therapeutic responses in patients. However, eventual relapse and resistance to bortezomib appear inevitable. Here, by integrating patient transcriptomic data with an analysis of calreticulin (CRT) protein interactors, we found that GABA type A receptor-associated protein (GABARAP) is a key player whose loss prevented tumor cell death from being perceived as immunogenic after bortezomib treatment. GABARAP is located on chromosome 17p, which is commonly deleted in patients with high risk MM. GABARAP deletion impaired the exposure of the eat-me signal CRT on the surface of dying MM cells in vitro and in vivo, thus reducing tumor cell phagocytosis by dendritic cells and the subsequent antitumor T-cell response. Low GABARAP was independently associated with shorter survival in patients with MM and reduced tumor immune infiltration. Mechanistically, we found that GABARAP deletion blocked ICD signaling by decreasing autophagy and altering Golgi apparatus morphology, with consequent defects in the downstream vesicular transport of CRT. Conversely, upregulating autophagy using rapamycin restored Golgi morphology, CRT exposure, and ICD signaling in GABARAPKO cells undergoing bortezomib treatment. Therefore, coupling an ICD inducer, such as bortezomib, with an autophagy inducer, such as rapamycin, may improve patient outcomes in MM, in which low GABARAP in the form of del(17p) is common and leads to worse outcomes.
Journal of Clinical Oncology
Tarantino P, Tayob N, Isakoff SJ, Faggen M, Mulvey T, Constantine M, Tung N, Waks AG, DeMeo M, Burstein HJ, Partridge AH, Kurt BB, Mittendorf EA, Winer EP, Krop IE, Tolaney SM
PURPOSE: Long-term outcomes of patients with stage I human epidermal growth factor receptor 2 (HER2)-positive breast cancer receiving adjuvant trastuzumab emtansine (T-DM1) remain undefined, and prognostic predictors represent an unmet need.
METHODS: In the ATEMPT phase II trial, patients with stage I centrally confirmed HER2-positive breast cancer were randomly assigned 3:1 to adjuvant T-DM1 for 1 year or paclitaxel plus trastuzumab (TH). Coprimary objectives were to compare the incidence of clinically relevant toxicities between arms and to evaluate invasive disease-free survival (iDFS) with T-DM1. Correlative analyses included the HER2DX genomic tool, multiomic evaluations of HER2 heterogeneity, and predictors of thrombocytopenia.
RESULTS: After a median follow-up of 5.8 years, 11 iDFS events were observed in the T-DM1 arm, consistent with a 5-year iDFS of 97.0% (95% CI, 95.2 to 98.7). At 5 years, the recurrence-free interval (RFI) was 98.3% (95% CI, 97.0 to 99.7), the overall survival was 97.8% (95% CI, 96.3 to 99.3), and the breast cancer-specific survival was 99.4% (95% CI, 98.6 to 100). Comparable iDFS was observed with T-DM1 irrespective of tumor size, hormone receptor status, centrally determined HER2 immunohistochemical score, and receipt of T-DM1 for more or less than 6 months. Although ATEMPT was not powered for this end point, the 5-year iDFS in the TH arm was 91.1%. Among patients with sufficient tissue for HER2DX testing (n = 187), 5-year outcomes significantly differed according to HER2DX risk score, with better RFI (98.1% v 81.8%, hazard ratio [HR], 0.10, P = .01) and iDFS (96.3% v 81.8%, HR, 0.20, P = .047) among patients with HER2DX low-risk versus high-risk tumors, respectively.
CONCLUSION: Adjuvant T-DM1 for 1 year leads to outstanding long-term outcomes for patients with stage I HER2-positive breast cancer. A high HER2DX risk score predicted a higher risk of recurrence in ATEMPT.
Journal of Clinical Oncology
Nowak JA, Twombly T, Ma C, Zhao M, Ogino S, Meyerhardt JA
Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. Observational studies have associated aspirin or cyclooxygenase 2 (COX-2) inhibitor usage either before or after colorectal cancer diagnosis with lower risk of recurrence and suggest that PIK3CA mutational status is predictive of better response to COX-2 inhibition. To prospectively test whether adding the COX-2 inhibitor celecoxib to standard adjuvant chemotherapy reduces the risk of recurrence and improves survival, the National Cancer Institute sponsored the CALGB/SWOG 80702 trial (ClinicalTrials.gov identifier: NCT01150045) for patients with stage III resected colon cancer. Although the primary hypothesis for all patients did not show a statistically significant improvement in disease-free survival (DFS) with celecoxib, subgroup analysis by PIK3CA mutational status was a preplanned study. PIK3CA gain-of-function mutations were detected in 259 of 1,197 tumors with available whole-exome sequencing data. When stratified by PIK3CA status, patients with PIK3CA gain-of-function mutations treated with celecoxib exhibited improved DFS (adjusted hazard ratio [HR], 0.56 [95% CI, 0.33 to 0.96]) compared with PIK3CA wildtype patients (adjusted HR, 0.89 [95% CI, 0.70 to 1.14]), although the interaction test was nonsignificant (Pinteraction = .13). Overall survival was similarly improved for patients with PIK3CA gain-of-function mutations (adjusted HR, 0.44 [95% CI, 0.22 to 0.85]) compared with PIK3CA wildtype patients (adjusted HR, 0.94 [95% CI, 0.68 to 1.30]; Pinteraction = .04). Although the test for heterogeneity in DFS did not reach statistical significance, the results suggest potential utility of PIK3CA to consider selective usage of COX-2 inhibitors in addition to standard treatment for stage III colon cancer.
Journal of Clinical Oncology
Freedman RA, Hassett M
ASCO Rapid Recommendation Updates highlight revisions to select ASCO guideline recommendations as a response to the emergence of new and practice-changing data. The rapid updates are supported by an evidence review and follow the guideline development processes outlined in the ASCO Guideline Methodology Manual. The goal of these articles is to disseminate updated recommendations, in a timely manner, to better inform health practitioners and the public on the best available cancer care options. Guidelines and updates are not intended to substitute for independent professional judgment of the treating provider and do not account for individual variation among patients. See appendix for disclaimers and other important information (Appendix 1 and Appendix 2, online only).
Journal of Clinical Oncology
Kwak L, Ravi P, D'Amico AV, Regan MM, Xie W
PURPOSE: We sought to evaluate the prognostic impact of prostate-specific antigen (PSA) at 6 months after completion of radiotherapy (RT) in patients treated with RT alone, RT plus short-term (st; 3-6 months), and RT plus long-term (lt; 24-36 months) androgen-deprivation therapy (ADT).
PATIENTS AND METHODS: Individual patient data were obtained from 16 randomized trials evaluating RT ± ADT for localized prostate cancer (PCa) between 1987 and 2011. The lowest PSA recorded within 6 months after RT completion was identified and categorized as < or ?0.1 ng/mL. The primary outcomes were metastasis-free survival (MFS), PCa-specific mortality (PCSM), and overall survival (OS), from 12 months after random assignment.
RESULTS: Ninety-eight percent (n = 2,339/2,376) of patients allocated to RT alone, 84% (n = 4,756/5,658) allocated to RT + stADT, and 77% (n = 1,258/1,626) allocated to RT + ltADT had PSA ?0.1 ng/mL within 6 months after completing RT. PSA ?0.1 ng/mL was associated with lower MFS and OS and higher PCSM among patients allocated to RT ± ADT (RT - MFS: hazard ratio [HR], 2.24 [95% CI, 1.21 to 4.16]; PCSM: subdistribution hazard ratio [sHR], 1.82 [0.51 to 6.49]; OS: HR, 1.72 [0.97 to 3.05]; RT + stADT - MFS: HR, 1.27 [1.12 to 1.44]; PCSM: sHR, 2.10 [1.52 to 2.92]; OS: HR, 1.26 [1.11 to 1.44]; RT + ltADT - MFS: HR, 1.58 [1.27 to 1.96]; PCSM: sHR, 1.97 [1.11 to 3.49]; OS: HR, 1.59 [1.27 to 1.99]). Five-year MFS rates among patients allocated to RT, RT + stADT, and RT + ltADT were 91% versus 79%, 83% versus 76%, and 87% versus 74%, respectively, based on PSA < or ?0.1 ng/mL.
CONCLUSION: PSA ?0.1 ng/mL within 6 months after RT completion was prognostic for lt outcomes in patients treated with RT ± ADT for localized PCa. This can be used to counsel patients treated with RT ± ADT and in guiding clinical trial design evaluating novel systemic therapies with RT + ADT as well as (de)intensification strategies.
Journal of Clinical Oncology
Cutler C
The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice.
Journal of the National Cancer Institute
Ilcisin L, Shulman DS, Weil BR, Weldon CB, Aziz-Bose R, Greenzang KA, Dubois SG, Janeway KA, Bona K
BACKGROUND: Children living in poverty and those of marginalized race or ethnicity experience inferior disease outcomes across many cancers. Whether survival disparities exist in osteosarcoma is poorly defined. We investigated the association between race, ethnicity, and proxied poverty exposures and event-free and overall survival for children with nonmetastatic osteosarcoma receiving care on a cooperative group trial.
METHODS: We conducted a retrospective cohort study of US patients with nonmetastatic, osteosarcoma aged 5-21 years enrolled on the Children's Oncology Group trial AOST0331. Race and ethnicity were categorized to reflect historically marginalized populations, as Hispanic, non-Hispanic Black, non-Hispanic Other, and non-Hispanic White. Poverty was proxied at the household and neighborhood levels. Overall survival and event-free survival functions of time from trial enrollment were estimated using the Kaplan-Meier method. Hypotheses of associations between risks for event-free survival, death, and postrelapse death with race and ethnicity were assessed using log-rank tests.
RESULTS: Among 758 patients, 25.6% were household-poverty and 28.5% neighborhood-poverty exposed. Of the patients, 21% of children identified as Hispanic, 15.4% non-Hispanic Black, 5.3% non-Hispanic Other, and 54.0% non-Hispanic White. Neither household or neighborhood poverty nor race and ethnicity were statistically significantly associated with risks for event-free survival or death. Postrelapse risk for death differed statistically significantly across race and ethnicity with non-Hispanic Black patients at greatest risk (4-year postrelapse survival 35.7% Hispanic vs 13.0% non-Hispanic Black vs 43.8% non-Hispanic Other vs 38.9% non-Hispanic White; P?=?.0046).
CONCLUSIONS: Neither proxied poverty exposures or race and ethnicity were associated with event-free survival or overall survival, suggesting equitable outcomes following frontline osteosarcoma trial-delivered therapy. Non-Hispanic Black children experienced statistically significant inferior postrelapse survival. Investigation of mechanisms underlying postrelapse disparities are paramount.
Nature Cell Biology
Loss of Kmt2c or Kmt2d Drives Brain Metastasis via KDM6A-Dependent Upregulation of MMP3
Seehawer M, Li Z, Nishida J, Foidart P, Reiter AH, Rojas-Jimenez E, Goyette MA, Yan P, Raval S, Munoz Gomez M, Cejas P, Long HW, Papanastasiou M, Polyak K
KMT2C and KMT2D, encoding histone H3 lysine 4 methyltransferases, are among the most commonly mutated genes in triple-negative breast cancer (TNBC). However, how these mutations may shape epigenomic and transcriptomic landscapes to promote tumorigenesis is largely unknown. Here we describe that deletion of Kmt2c or Kmt2d in non-metastatic murine models of TNBC drives metastasis, especially to the brain. Global chromatin profiling and chromatin immunoprecipitation followed by sequencing revealed altered H3K4me1, H3K27ac and H3K27me3 chromatin marks in knockout cells and demonstrated enhanced binding of the H3K27me3 lysine demethylase KDM6A, which significantly correlated with gene expression. We identified Mmp3 as being commonly upregulated via epigenetic mechanisms in both knockout models. Consistent with these findings, samples from patients with KMT2C-mutant TNBC have higher MMP3 levels. Downregulation or pharmacological inhibition of KDM6A diminished Mmp3 upregulation induced by the loss of histone-lysine N-methyltransferase 2 (KMT2) and prevented brain metastasis similar to direct downregulation of Mmp3. Taken together, we identified the KDM6A-matrix metalloproteinase 3 axis as a key mediator of KMT2C/D loss-driven metastasis in TNBC.
Nature Communications
Simultaneous Enhancement of Multiple Functional Properties Using Evolution-Informed Protein Design
Fram B, Su Y, Truebridge I, Riesselman AJ, Ingraham JB, Passera A, Thadani NN, Lim S, Stiffler MA, Marks DS, Bahl CD, Khan AR, Sander C, Gauthier NP
A major challenge in protein design is to augment existing functional proteins with multiple property enhancements. Altering several properties likely necessitates numerous primary sequence changes, and novel methods are needed to accurately predict combinations of mutations that maintain or enhance function. Models of sequence co-variation (e.g., EVcouplings), which leverage extensive information about various protein properties and activities from homologous protein sequences, have proven effective for many applications including structure determination and mutation effect prediction. We apply EVcouplings to computationally design variants of the model protein TEM-1 ?-lactamase. Nearly all the 14 experimentally characterized designs were functional, including one with 84 mutations from the nearest natural homolog. The designs also had large increases in thermostability, increased activity on multiple substrates, and nearly identical structure to the wild type enzyme. This study highlights the efficacy of evolutionary models in guiding large sequence alterations to generate functional diversity for protein design applications.
Biomedical Physics and Engineering Express
Lung Sparing in MR-Guided Non-Adaptive SBRT Treatment of Peripheral Lung Tumors
Lee HY, Lee G, Ferguson D, Hsu SH, Hu YH, Sudhyadhom A, Williams CL, Fitzgerald KJ, Kann BH, Kozono D, Leeman JE, Mak RH, Han Z
BioRxiv
Chukwu W, Lee S, Crane A, Zhang S, Webster S, Mittra I, Beroukhim R, Dubois F, Dalin S
Blood Advances
Hernandez-Lopez P, Vijaykumar T, Anand P, Frede J, Knoechel B, Lohr JG
Blood Advances
Shimony S, Liu Y, Schaefer EJ, Bystrom R, Lindsley RC, Chen EC, DeAngelo DJ, Neuberg DS, Stone RM, Stahl M
Blood Advances
Tabelecleucel for EBV+ PTLD After Allogeneic HCT or SOT in a Multicenter Expanded Access Protocol
Nikiforow S, Whangbo JS, Prockop S
BMJ
Viswanath K, Dryer E
Bone Marrow Transplantation
Kelkar AH, Groblewski N, Clancy D, Close SD, Sullivan LM, Cutler C, Abel GA
Cancer
Lu W, Giobbie-Hurder A, Tanasijevic A, Kassis SB, Bao T, Yang E, Bierer BE, Ligibel JA
Cancer Research
Single-Stranded DNA Gap Accumulation is a Functional Biomarker for USP1 Inhibitor Sensitivity
da Costa AABA, Somuncu O, Ravindranathan R, Mukkavalli S, Martignetti DB, Nguyen H, Jiao Y, Lamarre BP, Sadatrezaei G, Moreau L, Liu J, Iyer DR, Lazaro JB, Shapiro GI, Parmar K, D'Andrea AD
Cell Genomics
Tan KT, Slevin MK, Leibowitz ML, Garrity-Janger M, Li H, Meyerson M
Cell Host and Microbe
Richmond-Buccola D, Hobbs SJ, Garcia JM, Toyoda H, Gao J, Shao S, Lee ASY, Kranzusch PJ
Cell Reports
Endogenous p53 Inhibitor TIRR Dissociates Systemic Metabolic Health from Oncogenic Activity
Tsaousidou E, Drané P, Lee GY, Bahour N, Wang ZB, Deng S, Cao Z, Huang K, He Y, Güney E, Parmar K, Fendler W, Chowdhury D, Hotam??l?gil GS
Cell Reports
Epigenomic Signatures of Sarcomatoid Differentiation to Guide the Treatment of Renal Cell Carcinoma
El Zarif T, Semaan K, Eid M, Seo JH, Garinet S, Davidsohn MP, Sahgal P, Fortunato B, Canniff J, Lakshminarayanan G, Savignano H, Lyons K, Matar S, Saad E, Saliby RM, Cordeiro P, Zhang Z, El Ahmar N, Laimon YN, Labaki C, Shah V, Freeman D, O'Toole J, Lee GM, Pomerantz M, Signoretti S, Van Allen EM, Xie W, Berchuck JE, Viswanathan SR, Choueiri TK, Freedman ML, Baca SC
Cell Reports
Freeburg SH, Shwartz A, Kemény LV, Smith CJ, Weeks O, Miller BM, PenkoffLidbeck N, Fisher DE, Goessling W
Cell Systems
On Knowing a Gene: A Distributional Hypothesis of Gene Function
Kwon JJ, Pan J, Hahn WC, Zitnik M
ChemMedChem
Structural Analysis of the Macrocyclic Inhibitor BI-4020 Binding to EGFR Kinase
Beyett TS, Rana JK, Schaeffner IK, Eck MJ
Circulation
Induction of DEPP1 by HIF Mediates Multiple Hallmarks of Ischemic Cardiomyopathy
Wyant GA, Jiang Q, Singh M, Qayyum S, Levrero C, Maron BA, Kaelin WG Jr
Clinical Cancer Research
El Zarif T, Meador CB, Qiu X, Seo JH, Davidsohn MP, Savignano H, Lakshminarayanan G, McClure HM, Canniff J, Fortunato B, Li R, Banwait MK, Semaan K, Eid M, Long H, Hung YP, Mahadevan NR, Barbie DA, Oser MG, Piotrowska Z, Choueiri TK, Freedman ML, Berchuck JE
Future Oncology
Tolaney SM, Lynce F, Parsons HA, Partridge AH
Journal of Cachexia, Sarcopenia, and Muscle
Ligibel JA, Meyerhardt JA
Journal of Cancer Survivorship
Arm Morbidity and Financial Difficulty in Breast Cancer Survivors
Myers SP, Laws A, Dominici LS, Grossmith S, Mittendorf EA, King TA
Journal of Clinical Endocrinology and Metabolism
Sehgal K, Liu M, ONeill A, Pappa T, Haddad R
JCI Insight
Mather RV, Rowell TR, Obuchowski S, Walensky LD
JCO Oncology Practice
Fletcher KM, Revette A, Enzinger A, Biller L, Brais L, Arsenault B, McCleary N, Chan J, Boyle K, Meyerhardt JA, Ng K
Nature Microbiology
Interactions Between Diet and Gut Microbiota in Cancer
Nakatsu G, Andreeva N, MacDonald MH, Garrett WS
Neuro-Oncology
Touat M, Huang RY, Youssef G, Wen PY