Welcome to Dana-Farber's Research News
August 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.
Cell
Ricciuti B, Alessi JV, Wang X, Li YY, Vaz VR, Gupta H, Pecci F, Barrichello A, Lamberti G, Nguyen T, Lindsay J, Sharma B, Felt K, Rodig SJ, Nishino M, Sholl LM, Barbie DA, Cherniack AD, Meyerson M, Jänne PA, Schoenfeld AJ, Awad MM, Luo J
BACKGROUND: Allele-specific KRAS inhibitors are an emerging class of cancer therapies. KRAS mutant (KRASMUT) non-small cell lung cancers (NSCLCs) exhibit heterogeneous outcomes, driven by differences in underlying biology shaped by co-mutations. In contrast to KRASG12C NSCLC, KRASG12D NSCLC is associated with low/never-smoking status and is largely uncharacterized.
METHODS: Clinicopathologic and genomic information were collected from patients with NSCLCs harboring a KRAS mutation at Dana-Farber Cancer Institute (DFCI), Memorial Sloan Kettering Cancer Center (MSKCC), MD Anderson Cancer Center (MDACC) and Imperial College of London (ICL). Multiplexed immunofluorescence for CK7, PD-1, PD-L1, Foxp3, and CD8 was performed on a subset of samples with available tissue at the DFCI. Clinical outcomes to PD-(L)1 inhibition +/- chemotherapy were analyzed according to KRAS mutation subtype.
RESULTS: Of 2,327 patients with KRAS-mutated (KRASMUT) NSCLC, 15% (n=354) harbored KRASG12D. Compared to KRASnon-G12D NSCLC, KRASG12D NSCLC had a lower pack-year (py) smoking history (median 22.5 py vs 30.0 py, p<0.0001) and was enriched in never smokers (22% versus 5%, p<0.0001). KRASG12D had lower PD-L1 tumor proportion score (TPS) (median 1% vs 5%, p<0.01) and lower tumor mutation burden (TMB) compared to KRASnon-G12D (median 8.4 v 9.9 mt/Mb, p<0.0001). Of samples which underwent multiplexed immunofluorescence, KRASG12D had lower intratumoral and total CD8+PD1+ T cells (p<0.05). Among 850 patients with advanced KRASMUT NSCLC who received PD-(L)1 based therapies, KRASG12D was associated with a worse objective response rate (15.8% versus 28.4%, p=0.03), progression-free survival (PFS HR 1.51 [95%CI 1.45-2.00], p=0.003), and overall survival (OS HR 1.45 [1.05-1.99], p=0.02) to PD-(L)1 inhibition alone but not to chemo-immunotherapy combinations (ORR 30.6% versus 35.7%, p=0.51; PFS HR 1.28 [95%CI 0.92-1.77], p=0.13; OS HR 1.36 [95%CI 0.95-1.96], p=0.09) compared to KRASnon-G12D.
CONCLUSION: KRASG12D lung cancers harbor distinct clinical, genomic, and immunologic features compared to other KRAS mutated lung cancers and worse outcomes to PD-(L)1 blockade. Drug development for KRASG12D lung cancers will have to take these differences into account.
Cancer Discovery
Navigating the HER2-Low Paradigm in Breast Oncology: New Standards, Future Horizons
Tarantino P, Tolaney SM
The confirmation of the HER2-low paradigm is expected to have a major impact in breast oncology. About half of all breast cancers harbor HER2-low expression, which can be targeted with the anti-HER2 antibody-drug conjugate trastuzumab deruxtecan (T-DXd), leading to a relevant survival benefit in the metastatic setting. Given this observation, treatment algorithms for both hormone receptor-positive and triple-negative breast cancer are expected to significantly evolve in the next future. Several challenges, however, remain in the interpretation of HER2-low expression related to its biological role, its pathologic diagnosis, and the definition itself of HER2-low. In this article, we recapitulate the current knowledge on HER2-low breast cancer, discussing whether it should be considered a distinct subtype, how it should be implemented in the clinic, and how its definition may evolve in the coming years with the evolution of our clinical and translational knowledge.
Cell
Cancer Vaccines: Building a Bridge Over Troubled Waters
Sellars MC, Wu CJ, Fritsch EF
Cancer vaccines aim to direct the immune system to eradicate cancer cells. Here we review the essential immunologic concepts underpinning natural immunity and highlight the multiple unique challenges faced by vaccines targeting cancer. Recent technological advances in mass spectrometry, neoantigen prediction, genetically and pharmacologically engineered mouse models, and single-cell omics have revealed new biology, which can help to bridge this divide. We particularly focus on translationally relevant aspects, such as antigen selection and delivery and the monitoring of human post-vaccination responses, and encourage more aggressive exploration of novel approaches.
JAMA Oncology
Konstantinopoulos PA, Gockley AA, Xiong N, Krasner C, Horowitz N, Campos S, Wright AA, Liu JF, Shea M, Yeku O, Castro C, Polak M, Lee EK, Sawyer H, Bowes B, Cheng SC, Tayob N, Bouberhan S, Spriggs D, Penson RT, Nucci MR, Matulonis UA
IMPORTANCE: Although the activity of pembrolizumab and lenvatinib (the only US Food and Drug Administration-approved immunotherapy for mismatch repair proficient endometrial cancer [MMRP EC]) is compelling, there are no biomarkers of response and most patients do not tolerate, do not respond to, or develop resistance to this regimen, highlighting the need for additional, potentially biomarker-driven therapeutic approaches for patients with recurrent MMRP EC.
OBJECTIVE: To assess the potential positive outcomes and safety of the combination of the polyadenosine diphosphate-ribose polymerase inhibitor talazoparib and the programmed cell death ligand 1 (PD-L1) inhibitor avelumab in recurrent MMRP EC.
DESIGN, SETTINGS, AND PARTICIPANTS: This investigator-initiated, open-label, single-arm, 2-stage, phase 2 study nonrandomized controlled trial patients at 4 institutions in the US. Key eligibility criteria included measurable disease, unlimited prior therapies, and all endometrial cancer histologies.
INTERVENTIONS: Talazoparib, 1 mg, orally, daily, and avelumab, 10 mg/kg, intravenously, every 2 weeks, were administered until disease progression or unacceptable toxic effects.
MAIN OUTCOMES AND MEASURES: Statistical considerations were developed for 2 coprimary objectives of objective response rate and rate of progression-free survival at 6 months, with a 2-stage design that allowed for early discontinuation for futility. Prespecified exploratory objectives included the association of immunogenomic features (determined by targeted-panel next-generation sequencing and immunohistochemistry) with activity.
RESULTS: Thirty-five female patients (mean [SD] age, 67.9 [8.41] years) received protocol therapy; 9 (25.7%) derived clinical benefit after meeting at least 1 of the 2 coprimary end points. Four patients (11.4%) exhibited confirmed objective response rates (4 partial responses), and 8 (22.9%) survived progression free at 6 months. The most common grade 3 and 4 treatment-related toxic effects were anemia (16 [46%]), thrombocytopenia (10 [29%]), and neutropenia (4 [11%]); no patient discontinued receipt of therapy because of toxic effects. Tumors with homologous recombination repair alterations were associated with clinical benefit from treatment with avelumab and talazoparib. Tumor mutational burden, tumor-infiltrating lymphocytes, and PD-L1 status were not associated with clinical benefit.
CONCLUSIONS AND RELEVANCE: The results of this nonrandomized controlled trial suggest that treatment with avelumab and talazoparib demonstrated a favorable toxic effect profile and met the predetermined criteria to be considered worthy of further evaluation in MMRP EC. Immunogenomic profiling provided insights that may inform ongoing and future studies of polyadenosine diphosphate-ribose polymerase and PD-L1 inhibitor combinations in endometrial cancer.
TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02912572.
Journal of Clinical Oncology
A Process Framework for Ethically Deploying Artificial Intelligence in Oncology
Hantel A, Clancy DD, Kehl KL, Marron JM, Van Allen EM, Abel GA
Artificial Intelligence (AI) is an emerging technology that uses complex algorithms to arrive at an outcome over a range of circumstances, leveraging the ability of computer systems to perform tasks that would usually require human levels of intelligence. The use of AI in cancer care is rapidly expanding: a May 2022 PubMed search of the term cross-referenced with cancer revealed approximately 26,000 citations, with more than 60% published in the past five years. Ethical considerations for AI in oncology include patient equity, privacy, and autonomy; the roles of human- and machine-based judgment; and the patient-oncologist relationship. Relative to other parts of medicine, the implications of oncology AI are outsized, and some are idiosyncratic. Oncology AI tools apply to not one but two genomes (germline and somatic); can greatly complicate the existing weight of bias, discrimination, and structural racism in cancer care; and can subtly undermine patient and physician autonomy, leading to cancer care that is algorithmic rather than patient-centered. These diverse concerns, in the context of unreserved enthusiasm for AI, challenge a future where oncology AI is both widely implemented and ethically acceptable. We propose that adapting a process-focused approach for deploying AI in cancer care, such as the accountability for reasonableness framework (A4R), can address these concerns and realize a future where oncology AI is ethically deployed.
Journal of Clinical Oncology
Yurgelun MB
The vast majority of patients with pancreatic cancer (pancreatic ductal adenocarcinoma [PDAC]) are diagnosed in the unresectable and/or metastatic setting where 5-year survival is < 5%, although long-term cure is possible when PDAC is detected early. Individuals with inherited PDAC risk are thus ideal candidates in whom to study/develop surveillance strategies. Studies have shown that 4%-20% of individuals with PDAC harbor pathogenic germline variants (PGVs) in PDAC susceptibility genes (Table 1). Approximately 10% of individuals with PDAC have significant clustering of PDAC diagnoses in their family (usually without identifiable PGVs), which has been labeled familial pancreatic cancer.
Molecular Cell
TOPBPing up DSBs with PARylation
Roychoudhury S, Chowdhury D
Zhao et al. (2022) demonstrate that HIV Tat-specific factor 1, an RPA PARylation reader, recruits Topoisomerase II?-binding protein 1 to double-strand break sites specifically in the S phase of the cell cycle to promote homologous recombination.
Nature
Cryo-EM Structure of an Active Bacterial TIR-STING Filament Complex
Morehouse BR, Yip MCJ, Keszei AFA, McNamara-Bordewick NK, Shao S, Kranzusch PJ
Stimulator of interferon genes (STING) is an antiviral signalling protein that is broadly conserved in both innate immunity in animals and phage defence in prokaryotes1-4. Activation of STING requires its assembly into an oligomeric filament structure through binding of a cyclic dinucleotide4-13, but the molecular basis of STING filament assembly and extension remains unknown. Here we use cryogenic electron microscopy to determine the structure of the active Toll/interleukin-1 receptor (TIR)-STING filament complex from a Sphingobacterium faecium cyclic-oligonucleotide-based antiphage signalling system (CBASS) defence operon. Bacterial TIR-STING filament formation is driven by STING interfaces that become exposed on high-affinity recognition of the cognate cyclic dinucleotide signal c-di-GMP. Repeating dimeric STING units stack laterally head-to-head through surface interfaces, which are also essential for human STING tetramer formation and downstream immune signalling in mammals5. The active bacterial TIR-STING structure reveals further cross-filament contacts that brace the assembly and coordinate packing of the associated TIR NADase effector domains at the base of the filament to drive NAD+ hydrolysis. STING interface and cross-filament contacts are essential for cell growth arrest in vivo and reveal a stepwise mechanism of activation whereby STING filament assembly is required for subsequent effector activation. Our results define the structural basis of STING filament formation in prokaryotic antiviral signaling.
Nature Communications
Structural Basis of Human TREX1 DNA Degradation and Autoimmune Disease
Richmond-Buccola D, Kranzusch PJ
TREX1 is a cytosolic DNA nuclease essential for regulation of cGAS-STING immune signaling. Existing structures of mouse TREX1 establish a mechanism of DNA degradation and provide a key model to explain autoimmune disease, but these structures incompletely explain human disease-associated mutations and have limited ability to guide development of small-molecule therapeutics. Here we determine crystal structures of human TREX1 in apo and DNA-bound conformations that provide high-resolution detail of all human-specific features. A 1.25 A structure of human TREX1 establishes a complete model of solvation of the exonuclease active site and a 2.2 A structure of the human TREX1-DNA complex enables identification of specific substitutions involved in DNA recognition. We map each TREX1 mutation associated with autoimmune disease and establish distinct categories of substitutions predicted to impact enzymatic function, protein stability, and interaction with cGAS-DNA liquid droplets. Our results explain how human-specific substitutions regulate TREX1 function and provide a foundation for structure-guided design of TREX1 therapeutics.
Annals of Surgical Oncology
Kantor O, Burstein HJ, King TA, Winer EP, Mittendorf EA
Blood Advances
Tsai HK, Gibson CJ, Murdock HM, Davineni P, Harris MH, Kim AS, Nardi V, Lindsley RC
Blood Advances
Improving NK Cell Function in Multiple Myeloma with NKTR-255, a Novel Polymer-Conjugated Human IL-15
Alonso Fernandez R, Encinas J, Pierre-Louis L, Yao Y, Xu Y, Mu S, Prabhala RH, Anderson KC, Munshi NC, Fulciniti M
Blood Cancer Journal
BRD9 Degraders as Chemosensitizers in Acute Leukemia and Multiple Myeloma
Weisberg E, Chowdhury B, Meng C, Case AE, Ni W, Garg S, Sattler M, Sanchez D, Toure A, Stone RM, Galinsky I, Winer E, Griffin JD
BMJ Open
Lakin JR, Zupanc SN, Lindvall C, Moseley ET, Das S, Sciacca K, Volandes A
Breast Cancer Research and Treatment
Freedman RA, Revette AC, Gagnon H, Perilla-Glen A, Kokoski M, Hussein SO, Leone E, Hixon N, Lovato R, Loeser W, Lin NU, Minami CA, LeStage B, Faggen M, Poorvu PD, McKenna J, Keating NL, Schonberg MA
Cancers
Engineered Microphysiological Systems for Testing Effectiveness of Cell-Based Cancer Immunotherapies
Campisi M, Shelton SE, Chen M, Barbie DA, Knelson EH
Clinical and Translational Radiation Oncology
Perez K, Jacene H, Hornick JL, Ma C, Vaz N, Brais LK, Alexander H, Baddoo W, Astone K, Chan JA
Endocrine-Related Cancer
SDHx Mutations and Temozolomide in Malignant Pheochromocytoma and Paraganglioma
Perez K, Jacene H, Hornick JL, Ma C, Vaz N, Brais LK, Alexander H, Baddoo W, Astone K, Chan JA
Haematologica
PI3K Inhibitors in Chronic Lymphocytic Leukemia: Where Do We Go from Here?
Brown JR
Haematologica
Baumeister SHC
Head and Neck
Interventions for Head and Neck Cancer Survivors: Systematic Review
Margalit DN, Nekhlyudov L
International Journal of Cancer
Ma C, Ng K, Giovannucci E, Mayer RJ, Meyerhardt JA
JAMA Open Network
Farina EG, Revette A, Haakenstad EK, Cleveland JLF, Allende R, Hassett M, Schrag D, McCleary NJ
Journal of the American Medical Informatics Association
21st Century Cures Act: Ethical Recommendations for New Patient-Facing Products
Durieux BN, Lindvall C
Journal of Cancer Survivorship
Chevalier LL, Blackmon JE, Bober SL, Roman A, Chang G, Recklitis CJ
JAMIA Open
McCleary NJ, Haakenstad EK, Cleveland JLF, Manni M, Hassett MJ, Schrag D
Leukemia and Lymphoma
Said JT, Sun T, Larocca C, Virgen CA, Kupper TS, Fisher DC, Devlin PM, Elco CP, Song JS, LeBoeuf NR