Welcome to Dana-Farber's Research News
September 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 August 16 through August 31.
If you are a Dana-Farber faculty member and you think your paper is missing from Research News, please let us know by emailing dfciresearchnews@dfci.harvard.edu.
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Cell Animal and Bacterial Viruses Share Conserved Mechanisms of Immune Evasion Hobbs SJ, Kranzusch PJ Animal and bacterial cells sense and defend against viral infections using evolutionarily conserved antiviral signaling pathways. Here, we show that viruses overcome host signaling using mechanisms of immune evasion that are directly shared across the eukaryotic and prokaryotic kingdoms of life. Structures of animal poxvirus proteins that inhibit host cGAS-STING signaling demonstrate architectural and catalytic active-site homology shared with bacteriophage Acb1 proteins, which inactivate CBASS anti-phage defense. In bacteria, phage Acb1 proteins are viral enzymes that degrade host cyclic nucleotide immune signals. Structural comparisons of poxvirus protein-2'3'-cGAMP and phage Acb1-3'3'-cGAMP complexes reveal a universal mechanism of host nucleotide immune signal degradation and explain kingdom-specific additions that enable viral adaptation. Chimeric bacteriophages confirm that animal poxvirus proteins are sufficient to evade immune signaling in bacteria. Our findings identify a mechanism of immune evasion conserved between animal and bacterial viruses and define shared rules that explain host-virus interactions across multiple kingdoms of life. |
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JAMA Oncology Breast Cancer Index in Premenopausal Women with Early-Stage Hormone Receptor-Positive Breast Cancer Regan MM IMPORTANCE: Adjuvant ovarian function suppression (OFS) with oral endocrine therapy improves outcomes for premenopausal patients with hormone receptor-positive (HR+) breast cancer but adds adverse effects. A genomic biomarker for selecting patients most likely to benefit from OFS-based treatment is lacking. OBJECTIVE: To assess the predictive and prognostic performance of the Breast Cancer Index (BCI) for OFS benefit in premenopausal women with HR+ breast cancer. DESIGN, SETTING, AND PARTICIPANTS: This prospective-retrospective translational study used all available tumor tissue samples from female patients from the Suppression of Ovarian Function Trial (SOFT). These individuals were randomized to receive 5 years of adjuvant tamoxifen alone, tamoxifen plus OFS, or exemestane plus OFS. BCI testing was performed blinded to clinical data and outcome. The a priori hypothesis was that BCI HOXB13/IL17BR ratio (BCI[H/I])-high tumors would benefit more from OFS and high BCI portended poorer prognosis in this population. Settings spanned multiple centers internationally. Participants included premenopausal female patients with HR+ early breast cancer with specimens in the International Breast Cancer Study Group tumor repository available for RNA extraction. Data were collected from December 2003 to April 2021 and were analyzed from May 2022 to October 2022. MAIN OUTCOMES AND MEASURES: Primary end points were breast cancer-free interval (BCFI) for the predictive analysis and distant recurrence-free interval (DRFI) for the prognostic analyses. RESULTS: Tumor specimens were available for 1718 of the 3047 female patients in the SOFT intention-to-treat population. The 1687 patients (98.2%) who had specimens that yielded sufficient RNA for BCI testing represented the parent trial population. The median (IQR) follow-up time was 12 (10.5-13.4) years, and 512 patients (30.3%) were younger than 40 years. Tumors were BCI(H/I)-low for 972 patients (57.6%) and BCI(H/I)-high for 715 patients (42.4%). Patients with tumors classified as BCI(H/I)-low exhibited a 12-year absolute benefit in BCFI of 11.6% from exemestane plus OFS (hazard ratio [HR], 0.48 [95% CI, 0.33-0.71]) and an absolute benefit of 7.3% from tamoxifen plus OFS (HR, 0.69 [95% CI, 0.48-0.97]) relative to tamoxifen alone. In contrast, patients with BCI(H/I)-high tumors did not benefit from either exemestane plus OFS (absolute benefit, -0.4%; HR, 1.03 [95% CI, 0.70-1.53]; P for interaction?=?.006) or tamoxifen plus OFS (absolute benefit, -1.2%; HR, 1.05 [95% CI, 0.72-1.54]; P for interaction?=?.11) compared with tamoxifen alone. BCI continuous index was significantly prognostic in the N0 subgroup for DRFI (n?=?1110; P?=?.004), with 12-year DRFI of 95.9%, 90.8%, and 86.3% in BCI low-risk, intermediate-risk, and high-risk N0 cancers, respectively. CONCLUSIONS AND RELEVANCE: In this prospective-retrospective translational study of patients enrolled in SOFT, BCI was confirmed as prognostic in premenopausal women with HR+ breast cancer. The benefit from OFS-containing adjuvant endocrine therapy was greater for patients with BCI(H/I)-low tumors than BCI(H/I)-high tumors. BCI(H/I)-low status may identify premenopausal patients who are likely to benefit from this more intensive endocrine therapy. |
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JAMA Oncology Neoadjuvant Immunotherapy—From Trials to Practice Mittendorf EA, Tolaney SM Immunotherapy, including immune checkpoint inhibition, is a pillar of cancer care with approvals for use in multiple tumor types. In breast cancer, the immune checkpoint inhibitor (ICI) pembrolizumab is approved by the US Food and Drug Administration (FDA) in combination with chemotherapy for programmed cell death ligand 1 (PD-L1)–positive (PD-L1+) metastatic triple-negative breast cancer (TNBC) and in early-stage TNBC regardless of the tumor’s PD-L1 status. In early-stage disease, the combination is approved in the neoadjuvant setting (with continuation of pembrolizumab as adjuvant therapy) based on the KEYNOTE-522 trial that showed an increased pathologic complete response (pCR) rate and improved event-free survival (EFS) and overall survival for patients receiving immunotherapy.1-3 As detailed in the Villacampa et al4 meta-analysis, additional trials have investigated other ICI in early-stage TNBC, and among 2075 patients with TNBC included in the intention-to-treat population, the addition of an ICI resulted in an increase in pCR rate from 46.6% to 59.9% (difference of 13.3%; odds ratio [OR], 1.64; 95% CI, 1.49-2.36). The magnitude of benefit was similar regardless of the tumor’s PD-L1 status, supporting ICI use in early-stage TNBC without the need to assess an individual patient’s tumor for PD-L1 expression. Individual patient data in this meta-analysis also showed that ICI use improved EFS (hazard ratio [HR], 0.69; 95% CI, 0.57-0.84). |
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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. |
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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. |
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Journal of the National Cancer Institute Ma C, Meyerhardt JA BACKGROUND: Both inflammation and insufficient physical inactivity contribute to individual-level risk of disease recurrence and death in stage III colon cancer. The extent to which increased inflammatory risk can be offset by sufficient physical activity remains unknown. METHODS: This cohort study was nested within the CALGB/SWOG 80702 (Alliance) randomized trial. Inflammatory burden was quantified by high-sensitivity C-reactive protein, interleukin-6, and soluble tumor necrosis factor-? receptor 2 after recovery from tumor resection. Physical activity was measured during and after postoperative chemotherapy. The primary endpoint was disease-free survival. RESULTS: The 3-year disease-free survival rate was 88.4% among patients with low inflammation and sufficient physical activity (referent group for all comparisons), 84.9% with low inflammation and insufficient physical activity [absolute risk difference (RD): -3.5%, 95% Confidence Interval (CI): -11.3, 4.3; P?=?.38], 78.0% with intermediate inflammation and insufficient physical activity (RD: -10.4%, 95% CI: -17.4, -3.3; P?=?.007), and 79.7% with high inflammation and insufficient physical activity (RD: -8.7%, 95% CI: -15.7, -1.6; P?=?.022). In contrast, the 3-year disease-free survival rate was 87.3% among patients with intermediate inflammation and sufficient physical activity (RD: -1.1%, 95% CI: -7.5, 5.3; P?=?.74) and 84.4% with high inflammation and sufficient physical activity (RD: -4.0%, 95% CI: -12.3, 4.3; P?=?.34). CONCLUSION: In this observational study of stage III colon cancer patients, physical activity was associated with improved disease-free survival despite high inflammation. Patients with intermediate or high inflammation who were physically active had disease-free survival rates that were not statistically significantly different from those with low inflammation. |
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Journal of the National Cancer Institute Plant-Based Diet and Survival Among Patients with Metastatic Colorectal Cancer Ma C, Ng K, Meyerhardt JA BACKGROUND: Plant-based diet is associated with better survival among patients with non-metastatic colorectal cancer (CRC), but its association in metastatic CRC is unknown. METHODS: Using an NCI-sponsored trial (CALGB/SWOG 80405), we included 1,284 patients who completed validated food frequency questionnaires at the initiation of metastatic CRC treatment. We calculated three indices: overall plant-based diet index (PDI), which emphasized consumption of all plant foods while reducing animal food intake; healthful plant-based diet index (hPDI), which emphasized consumption of healthful plant foods such as whole grains, fruits, and vegetables; and unhealthful plant-based diet index (uPDI), which emphasized consumption of less healthful plant foods such as fruit juices, refined grains, and sugar-sweetened beverages. We estimated the associations of three indices (quintiles) with overall survival (OS) and progression-free survival (PFS) using multivariable Cox proportional hazards regression. RESULTS: We observed 1,100 deaths and 1,204 progression events (median follow-up: 6.1?years). Compared to the lowest quintile, patients in the highest quintile of PDI had significantly better survival (HR for OS: 0.76 [0.62-0.94], P trend=0.004; PFS: 0.81 [0.66-0.99], P trend=0.09). Similar findings were observed for hPDI (HR for OS: 0.81 [0.65-1.01], P trend=0.053; PFS: 0.80 [0.65-0.98], P trend=0.04), whereas uPDI was not associated with worse survival (HR for OS: 1.16 [0.94-1.43], P trend=0.21; PFS: 1.12 [0.92-1.36], P trend=0.42). CONCLUSIONS: Our study suggests that plant-based diet, especially when rich in healthful plant foods, is associated with better survival among patients with metastatic CRC. The cause of survival benefits warrants further investigation. |
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Nature Biotechnology Cieri N, Hookeri N, Stromhaug K, Li L, Keating J, Stevens J, Kfuri-Rubens R, Shao Y, Kooshesh KA, Powell K, Ji H, Hernandez GM, Abelin J, Klaeger S, Forman C, Clauser KR, Sarkizova S, Braun DA, Penter L, Kim HT, Lane WJ, Oliveira G, Kean LS, Li S, Livak KJ, Carr SA, Keskin DB, Ho VT, Ritz J, Soiffer RJ, Neuberg D, Stewart C, Getz G, Wu CJ T cell alloreactivity against minor histocompatibility antigens (mHAgs)-polymorphic peptides resulting from donor-recipient (D-R) disparity at sites of genetic polymorphisms-is at the core of the therapeutic effect of allogeneic hematopoietic cell transplantation (allo-HCT). Despite the crucial role of mHAgs in graft-versus-leukemia (GvL) and graft-versus-host disease (GvHD) reactions, it remains challenging to consistently link patient-specific mHAg repertoires to clinical outcomes. Here we devise an analytic framework to systematically identify mHAgs, including their detection on HLA class I ligandomes and functional verification of their immunogenicity. The method relies on the integration of polymorphism detection by whole-exome sequencing of germline DNA from D-R pairs with organ-specific transcriptional- and proteome-level expression. Application of this pipeline to 220 HLA-matched allo-HCT D-R pairs demonstrated that total and organ-specific mHAg load could independently predict the occurrence of acute GvHD and chronic pulmonary GvHD, respectively, and defined promising GvL targets, confirmed in a validation cohort of 58 D-R pairs, for the prevention or treatment of post-transplant disease recurrence. |
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Nature Cancer Wei G, McFarland J, Lemke CT, Zhang W, Davis K, Poncet-Montange G, Roth J, Golub TR The MCL1 gene is frequently amplified in cancer and codes for the antiapoptotic protein myeloid cell leukemia 1 (MCL1), which confers resistance to the current standard of care. Therefore, MCL1 is an attractive anticancer target. Here we describe BRD-810 as a potent and selective MCL1 inhibitor and its key design principle of rapid systemic clearance to potentially minimize area under the curve-driven toxicities associated with MCL1 inhibition. BRD-810 induced rapid cell killing within 4?h in vitro but, in the same 4-h window, had no impact on cell viability or troponin I release in human induced pluripotent stem cell-derived cardiomyocytes, even at suprapharmacologic concentrations. In vivo BRD-810 induced efficacy in xenograft hematological and solid tumor models despite the short residence time of BRD-810 in plasma. In totality, our data support the hypothesis that short-term inhibition of MCL1 with BRD-810 can induce apoptosis in tumor cells while maintaining an acceptable safety profile. We, therefore, intend to advance BRD-810 to clinical trials. |
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Nature Communications RIOK2 Transcriptionally Regulates TRiC and Dyskerin Complexes to Prevent Telomere Shortening Ghosh S, Nguyen MT, Choi HE, Stahl M, Petsko GA, Glimcher LH Telomere shortening is a prominent hallmark of aging and is emerging as a characteristic feature of Myelodysplastic Syndromes (MDS) and Idiopathic Pulmonary Fibrosis (IPF). Optimal telomerase activity prevents progressive shortening of telomeres that triggers DNA damage responses. However, the upstream regulation of telomerase holoenzyme components remains poorly defined. Here, we identify RIOK2, a master regulator of human blood cell development, as a critical transcription factor for telomere maintenance. Mechanistically, loss of RIOK2 or its DNA-binding/transactivation properties downregulates mRNA expression of both TRiC and dyskerin complex subunits that impairs telomerase activity, thereby causing telomere shortening. We further show that RIOK2 expression is diminished in aged individuals and IPF patients, and it strongly correlates with shortened telomeres in MDS patient-derived bone marrow cells. Importantly, ectopic expression of RIOK2 alleviates telomere shortening in IPF patient-derived primary lung fibroblasts. Hence, increasing RIOK2 levels prevents telomere shortening, thus offering therapeutic strategies for telomere biology disorders. |
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New England Journal of Medicine Belzutifan Versus Everolimus for Advanced Renal-Cell Carcinoma Choueiri TK BACKGROUND: Belzutifan, a hypoxia-inducible factor 2? inhibitor, showed clinical activity in clear-cell renal-cell carcinoma in early-phase studies. METHODS: In a phase 3, multicenter, open-label, active-controlled trial, we enrolled participants with advanced clear-cell renal-cell carcinoma who had previously received immune checkpoint and antiangiogenic therapies and randomly assigned them, in a 1:1 ratio, to receive 120 mg of belzutifan or 10 mg of everolimus orally once daily until disease progression or unacceptable toxic effects occurred. The dual primary end points were progression-free survival and overall survival. The key secondary end point was the occurrence of an objective response (a confirmed complete or partial response). RESULTS: A total of 374 participants were assigned to belzutifan, and 372 to everolimus. At the first interim analysis (median follow-up, 18.4 months), the median progression-free survival was 5.6 months in both groups; at 18 months, 24.0% of the participants in the belzutifan group and 8.3% in the everolimus group were alive and free of progression (two-sided P?=?0.002, which met the prespecified significance criterion). A confirmed objective response occurred in 21.9% of the participants (95% confidence interval [CI], 17.8 to 26.5) in the belzutifan group and in 3.5% (95% CI, 1.9 to 5.9) in the everolimus group (P<0.001, which met the prespecified significance criterion). At the second interim analysis (median follow-up, 25.7 months), the median overall survival was 21.4 months in the belzutifan group and 18.1 months in the everolimus group; at 18 months, 55.2% and 50.6% of the participants, respectively, were alive (hazard ratio for death, 0.88; 95% CI, 0.73 to 1.07; two-sided P?=?0.20, which did not meet the prespecified significance criterion). Grade 3 or higher adverse events of any cause occurred in 61.8% of the participants in the belzutifan group (grade 5 in 3.5%) and in 62.5% in the everolimus group (grade 5 in 5.3%). Adverse events led to discontinuation of treatment in 5.9% and 14.7% of the participants, respectively. CONCLUSIONS: Belzutifan showed a significant benefit over everolimus with respect to progression-free survival and objective response in participants with advanced clear-cell renal-cell carcinoma who had previously received immune checkpoint and antiangiogenic therapies. Belzutifan was associated with no new safety signals. (Funded by Merck Sharp and Dohme, a subsidiary of Merck; LITESPARK-005 ClinicalTrials.gov number, NCT04195750.). |
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American Journal of Hospice and Palliative Care Zupanc SN, Volandes A, Penumarthy A, Lakin JR |
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Annals of Surgical Oncology ASO Visual Abstract: Potential Overtreatment of DCIS in Patients with Limited Life Expectancy Lorentzen EH, Chen YJ, Jin G, King TA, Mittendorf EA, Minami CA |
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Blood Advances COVID-19 Vaccination During Therapy in Relation to COVID-19 Death in CLL Brown JR |
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Cancer Androgen Deprivation Therapy and Postprostatectomy Radiation: What is the Optimal Duration? Yang DD, D'Amico AV |
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Cancer Snaman JM, Chen L, Mazzola E, Helton G, Feifer D, Rosenberg AR, Wolfe J |
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Cancer George S, Piantadosi S |
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Cancer Park KU, Lipsitz S, Dominici LS, Lynce F, Minami CA, Nakhlis F, Waks AG, Warren LE, Weissman JS, King TA, Mittendorf EA |
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Cancer Oppegaard KR, Hammer MJ |
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Developmental Cell Nucleotide Depletion Promotes Cell Fate Transitions by Inducing DNA Replication Stress Hsu PP, Hirz T, Abbott KL, Aziz N, Bjelosevic S, Paolino J, Ferreira R, Zhang H, Milosevic J, Schmidt DR, Chidley C, Pikman Y, Stegmaier K, Sykes DB, Vander Heiden MG |
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Health Communication The Relationship Between News Coverage of COVID-19 Misinformation and Online Search Behavior Douglas-Durham E, Emmons KM, Viswanath K |
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Hemato Richardson PG |
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International Journal of Molecular Sciences Sayan M, Chen LW, Yang DD, Moningi S, Leeman JE, Orio PF, Nguyen PL, D'Amico AV |
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Journal for ImmunoTherapy of Cancer Maloney AK, Giobbie-Hurder A, Katukota N, Ott PA, Hodi FS, Sussman TA, Silk AW, Haq R, Liu D, Insco M, Buchbinder EI |
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Journal of Integrative and Complementary Medicine Bao T |
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Nature Metabolism Cancer Tissue of Origin Constrains the Growth and Metabolism of Metastases Winter PS, Abbott KL, Morita S, Duda DG, Aguirre AJ, Wolpin BM, Yilmaz OH, Shalek AK, Vander Heiden MG |
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Nature Reviews Cancer Limiting Bias in AI Models for Improved and Equitable Cancer Care Gusev A |
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Nature Reviews Molecular Cell Biology Profiling Cell Identity and Tissue Architecture with Single-Cell and Spatial Transcriptomics Gulati GS |
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Neuro-Oncology Pereslete AM, Hughes ME, Martin AR, Files J, Nguyen K, Buckley L, Patel A, Moore A, Winer EP, Dillon D, Li T, Tolaney SM, Lin NU, Sammons SL |
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Neuro-Oncology Multimodal Deep Learning Improves Recurrence Risk Prediction in Pediatric Low-Grade Gliomas Mahootiha M, Tak D, Ye Z, Zapaishchykova A, Likitlersuang J, Climent Pardo JC, Boyd A, Vajapeyam S, Chopra R, Prabhu SP, Liu KX, Elhalawani H, Aerts HJWL, Bandopadhayay P, Ligon KL, Haas-Kogan D, Poussaint TY, Kann BH |
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Oncogene Hideshima T, Podar K, Chauhan D, Ishitsuka K, Mitsiades C, Tai YT, Hamasaki M, Raje N, Hideshima H, Munshi NC, Richardson PG, Anderson KC |
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Oncologist Genomic Landscape of Malignant Phyllodes Tumors Reveals Multiple Targetable Opportunities Sammons SL |
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Oncologist Liquid Biopsy in Renal Cell Carcinoma Machaalani M, Eid M, Semaan K, El Hajj Chehade R, Nawfal R, Baca SC, Choueiri TK |
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Science Advances Parsing Digital or Analog TCR Performance Through Piconewton Forces Akitsu A, Kobayashi E, Brazin KN, Mallis RJ, Duke-Cohan JS, Booker MA, Cinella V, Feng WW, Lee JJ, Tolstorukov MY, Lang MJ, Reinherz EL |
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Seminars in Oncology Nursing Moraitis AM, Hammer MJ |