Welcome to Dana-Farber's Research News
April 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 March 16 through March 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 ericd_schuller@dfci.harvard.edu.
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Blood
Frontline Treatment of Mantle Cell Lymphoma
Ryan CE, Armand P, LaCasce AS
Despite many recent therapeutic advances, mantle cell lymphoma (MCL) remains a largely incurable disease. Treatments for patients with relapsed/refractory (R/R) disease are limited in number and in response durability. Therefore, improving the efficacy of frontline (1L) treatment, and specifically maximizing the duration of first remission, remains of critical importance to obtain favorable long-term outcomes. As 1L treatments become more effective, improving tolerability is also becoming an increasingly realistic goal. Targeted agents, which are now mainstays of treatment in R/R MCL, are establishing new, paradigm-changing roles in frontline treatment. Here, we review data supporting current standard-of-care (SOC) approaches and explore six main areas of possible focus for advancement of 1L management: optimizing the chemoimmunotherapy (CIT) backbone, adding targeted agents to CIT, redefining the role of autologous stem cell transplantation (ASCT), improving maintenance therapy, using targeted agent combinations with omission of CIT, and employing MRD-guided therapy. We highlight several ongoing phase 3 trials that may soon impact frontline MCL management and outline some areas of necessary investigation as the field continues to strive towards a cure for this disease.
Blood
Loss of GABARAP Mediates Resistance to Immunogenic Chemotherapy in Multiple Myeloma
Morelli E, Johnstone M, Samur MK, Cifric S, Folino P, Vinaixa D, Favasuli VK, Maisano D, Talluri S, Prabhala RH, 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 anti-tumor 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 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 high-risk MM patients. 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 anti-tumor T cell response. Low GABARAP was independently associated with shorter MM patient survival 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, like bortezomib, with an autophagy inducer, like rapamycin, may improve patient outcomes in MM, where low GABARAP in the form of del(17p) is common and leads to worse outcomes.
Blood
Alvarez Calderon F, Kyrysyuk O, Wang H, Mathewson ND, Luoma AM, Ning X, Pyrdol J, Suvà ML, Wucherpfennig KW
The CD161 inhibitory receptor is highly upregulated by tumor-infiltrating T cells in multiple human solid tumor types, and its ligand, CLEC2D, is expressed by both tumor cells and infiltrating myeloid cells. Here, we assessed the role of the CD161 receptor in hematological malignancies. Systematic analysis of CLEC2D expression using the Cancer Cell Line Encyclopedia revealed that CLEC2D messenger RNA was most abundant in hematological malignancies, including B-cell and T-cell lymphomas as well as lymphocytic and myelogenous leukemias. CLEC2D protein was detected by flow cytometry on a panel of cell lines representing a diverse set of hematological malignancies. We, therefore, used yeast display to generate a panel of high-affinity, fully human CD161 monoclonal antibodies (mAbs) that blocked CLEC2D binding. These mAbs were specific for CD161 and had a similar affinity for human and nonhuman primate CD161, a property relevant for clinical translation. A high-affinity CD161 mAb enhanced key aspects of T-cell function, including cytotoxicity, cytokine production, and proliferation, against B-cell lines originating from patients with acute lymphoblastic leukemia, diffuse large B-cell lymphoma, and Burkitt lymphoma. In humanized mouse models, this CD161 mAb enhanced T-cell-mediated immunity, resulting in a significant survival benefit. Single cell RNA-seq data demonstrated that CD161 mAb treatment enhanced expression of cytotoxicity genes by CD4 T cells as well as a tissue-residency program by CD4 and CD8 T cells that is associated with favorable survival outcomes in multiple human cancer types. These fully human mAbs, thus, represent potential immunotherapy agents for hematological malignancies.
Journal of Clinical Oncology
Cemiplimab for Kidney Transplant Recipients with Advanced Cutaneous Squamous Cell Carcinoma
Hanna GJ, Dharanesswaran H, Giobbie-Hurder A, Harran JJ, Liao Z, Ruiz ES, Waldman AH, Schmults CD, Riella LV, Lizotte P, Paweletz CP, Chandraker AK, Murakami N, Silk AW
PURPOSE: Cemiplimab is approved for treating locally advanced or metastatic cutaneous squamous cell carcinoma (CSCC). Solid organ transplant recipients have been excluded from immunotherapy trials, given concern for allograft rejection despite their increased risk of skin cancers. Chronic immunosuppression is necessary to prevent organ rejection but may attenuate antitumor response with PD-1 inhibitors.
METHODS: We report a phase I study of cemiplimab for kidney transplant recipients (KTRs) with advanced CSCC. After cross-taper to a mammalian target of rapamycin (mTOR) inhibitor and pulsed dose corticosteroids (prednisone 40 mg once daily, the day before and on days 1-3 of each cycle, followed by 20 mg once daily on days 4-6, then 10 mg once daily until the day before each subsequent cycle), patients received cemiplimab 350 mg intravenously once every 3 weeks for up to 2 years and were assessed for response every 8 weeks. The primary end point was the rate of kidney rejection, with key secondary end points including rate and duration of response, and survival.
RESULTS: Twelve patients were treated. No kidney rejection or loss was observed. A response to cemiplimab was observed in five of 11 evaluable patients (46%; 90% CI, 22 to 73), including two with durable responses beyond a year. Median follow-up was 6.8 months (range, 0.7-29.8). Treatment-related grade 3 or greater adverse events occurred in five patients (42%), including diarrhea, infection, and metabolic disturbances. One patient died of angioedema and anaphylaxis attributed to mTOR inhibitor cross-taper.
CONCLUSION: mTOR inhibitor and corticosteroids represent a favorable immunosuppressive regimen for KTRs with advanced CSCC receiving immunotherapy. This combination resulted in durable antitumor responses with no kidney rejection events (funded by Regeneron Pharmaceuticals [ClinicalTrials.gov identifier: NCT04339062]).
Journal of Clinical Oncology
Mayer EL, Ren Y, Wagle N, Sinclair N, Faggen M, Block CC, Partridge AH, Chen WY, DeMeo M, Attaya V, Okpoebo A, Alberti J, Burstein HJ, Regan MM, Tolaney SM
PURPOSE: Cyclin-dependent kinase (CDK) 4/6 inhibitors (CDK4/6is) are an important component of treatment for hormone receptor-positive/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC), but it is not known if patients might derive benefit from continuation of CDK4/6i with endocrine therapy beyond initial tumor progression or if the addition of checkpoint inhibitor therapy has value in this setting.
METHODS: The randomized multicenter phase II PACE trial enrolled patients with hormone receptor-positive/HER2- MBC whose disease had progressed on previous CDK4/6i and aromatase inhibitor (AI) therapy. Patients were randomly assigned 1:2:1 to receive fulvestrant (F), fulvestrant plus palbociclib (F + P), or fulvestrant plus palbociclib and avelumab (F + P + A). The primary end point was investigator-assessed progression-free survival (PFS) in patients treated with F versus F + P.
RESULTS: Overall, 220 patients were randomly assigned between September 2017 and February 2022. The median age was 57 years (range, 25-83 years). Most patients were postmenopausal (80.9%), and 40% were originally diagnosed with de novo MBC. Palbociclib was the most common previous CDK4/6i (90.9%). The median PFS was 4.8 months on F and 4.6 months on F + P (hazard ratio [HR], 1.11 [90% CI, 0.79 to 1.55]; P = .62). The median PFS on F + P + A was 8.1 months (HR v F, 0.75 [90% CI, 0.50 to 1.12]; P = .23). The difference in PFS with F + P and F + P + A versus F was greater among patients with baseline ESR1 and PIK3CA alterations.
CONCLUSION: The addition of palbociclib to fulvestrant did not improve PFS versus fulvestrant alone among patients with hormone receptor-positive/HER2- MBC whose disease had progressed on a previous CDK4/6i plus AI. The increased PFS seen with the addition of avelumab warrants further investigation in this patient population.
Journal of the National Cancer Institute
Hantel A, Brunner AM, Uno H, Varela JC, Luskin MR, Rebbeck TR, Stone RM, Lathan CS, DeAngelo DJ, Abel GA
BACKGROUND: Clinical trial participation at Comprehensive Cancer Centers (CCC) is inequitable for minoritized race/ethnic groups with acute leukemia. CCCs care for a high proportion of adults with acute leukemia. It is unclear if participation inequities are due to CCC access, post-access enrollment, or both.
METHODS: We conducted a retrospective cohort study of adults with acute leukemia (2010-2019) residing within Massachusetts, the designated catchment area of the Dana-Farber/Harvard Cancer Center (DF/HCC). Individuals were categorized as non-Hispanic Asian (NHA), Black (NHB), White (NHW), Hispanic White (HW), or Other. Decomposition analyses assessed covariate contributions to disparities in (1) access to DF/HCC care and (2) post-access enrollment.
RESULTS: Of 3698 individuals with acute leukemia, 85.9% were NHW, 4.5% HW, 4.3% NHB, 3.7% NHA, and 1.3% Other. Access was lower for HW (age- and sex-adjusted OR 0.64 95%CI 0.45,0.90) and reduced post-access enrollment for HW (aOR 0.54 95%CI 0.34,0.86) and NHB (aOR 0.60 95%CI 0.39,0.92) compared to NHW. Payor and socioeconomic status (SES) accounted for 25.2% and 21.2% of the +1.1% absolute difference in HW access. Marital status and SES accounted for 8.0% and 7.0% of the -8.8% absolute disparity in HW enrollment; 76.4% of the disparity was unexplained. SES and marital status accounted for 8.2% and 7.1% of the -9.1% absolute disparity in NHB enrollment; 73.0% of the disparity was unexplained.
CONCLUSIONS: A substantial proportion of race/ethnic inequities in acute leukemia trial enrollment at CCCs are from post-access enrollment, the majority of which was not explained by sociodemographic factors.
JAMA Oncology
PARP Inhibitors for Breast Cancer Treatment: A Review
Morganti S, Giordano A, Garber JE, Lynce F
IMPORTANCE: Poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors have revolutionized the treatment of patients with germline BRCA1/2-associated breast cancer, representing the first targeted therapy capable of improving outcomes in patients with hereditary tumors. However, resistance to PARP inhibitors occurs in almost all patients.
OBSERVATIONS: This narrative review summarizes the biological rationale behind the use of PARP inhibitors in breast cancer, as well as the available evidence, recent progress, and potential future applications of these agents. Recent studies have shown that the benefit of PARP inhibitors extends beyond patients with germline BRCA1/2-associated metastatic breast cancer to patients with somatic BRCA1/2 variants and to those with germline PALB2 alterations. Moreover, these agents proved to be effective both in the metastatic and adjuvant settings. However, patients with metastatic breast cancer usually do not achieve the long-term benefit from PARP inhibitors observed in other tumor types. Mechanisms of resistance have been identified, but how to effectively target them is largely unknown. Ongoing research is investigating both novel therapeutics and new combination strategies to overcome resistance. PARP1-selective inhibitors, by sparing the hematological toxic effects induced by the PARP2 blockade, are promising agents to be combined with chemotherapy, antibody-drug conjugates, and other targeted therapies.
CONCLUSIONS AND RELEVANCE: Although the efficacy of PARP inhibitors is well established, many questions persist. Future research should focus on identifying predictive biomarkers and therapeutic strategies to overcome resistance. Integrating well-designed translational efforts into all clinical studies is thereby crucial to laying the groundwork for future insights from ongoing research.
Nature
Structure and Assembly of a Bacterial Gasdermin Pore
Johnson AG, Mayer ML, McNamara-Bordewick NK, Kranzusch PJ
In response to pathogen infection, gasdermin (GSDM) proteins form membrane pores that induce a host cell death process called pyroptosis1-3. Studies of human and mouse GSDM pores have revealed the functions and architectures of assemblies comprising 24 to 33 protomers4-9, but the mechanism and evolutionary origin of membrane targeting and GSDM pore formation remain unknown. Here we determine a structure of a bacterial GSDM (bGSDM) pore and define a conserved mechanism of pore assembly. Engineering a panel of bGSDMs for site-specific proteolytic activation, we demonstrate that diverse bGSDMs form distinct pore sizes that range from smaller mammalian-like assemblies to exceptionally large pores containing more than 50 protomers. We determine a cryo-electron microscopy structure of a Vitiosangium bGSDM in an active 'slinky'-like oligomeric conformation and analyse bGSDM pores in a native lipid environment to create an atomic-level model of a full 52-mer bGSDM pore. Combining our structural analysis with molecular dynamics simulations and cellular assays, our results support a stepwise model of GSDM pore assembly and suggest that a covalently bound palmitoyl can leave a hydrophobic sheath and insert into the membrane before formation of the membrane-spanning ?-strand regions. These results reveal the diversity of GSDM pores found in nature and explain the function of an ancient post-translational modification in enabling programmed host cell death.
Nature Chemical Biology
Ubiquitin-Specific Proximity Labeling for the Identification of E3 Ligase Substrates
Huang HT, Lumpkin RJ, Tsai RW, Su S, Zhao X, Xiong Y, Chen J, Mageed N, Donovan KA, Fischer ES, Sellers WR
Protein ubiquitylation controls diverse processes within eukaryotic cells, including protein degradation, and is often dysregulated in disease. Moreover, small-molecule degraders that redirect ubiquitylation activities toward disease targets are an emerging and promising therapeutic class. Over 600 E3 ubiquitin ligases are expressed in humans, but their substrates remain largely elusive, necessitating the development of new methods for their discovery. Here we report the development of E3-substrate tagging by ubiquitin biotinylation (E-STUB), a ubiquitin-specific proximity labeling method that biotinylates ubiquitylated substrates in proximity to an E3 ligase of interest. E-STUB accurately identifies the direct ubiquitylated targets of protein degraders, including collateral targets and ubiquitylation events that do not lead to substrate degradation. It also detects known substrates of E3 ligase CRBN and VHL with high specificity. With the ability to elucidate proximal ubiquitylation events, E-STUB may facilitate the development of proximity-inducing therapeutics and act as a generalizable method for E3-substrate mapping.
Nature Communications
Lynce F, Tarantino P, Tolaney SM, Parsons HA
Chemotherapy and immune checkpoint inhibitors have a role in the post-neoadjuvant setting in patients with triple-negative breast cancer (TNBC). However, the effects of nivolumab, a checkpoint inhibitor, capecitabine, or the combination in changing peripheral immunoscore (PIS) remains unclear. This open-label randomized phase II OXEL study (NCT03487666) aimed to assess the immunologic effects of nivolumab, capecitabine, or the combination in terms of the change in PIS (primary endpoint). Secondary endpoints included the presence of ctDNA, toxicity, clinical outcomes at 2-years and association of ctDNA and PIS with clinical outcomes. Forty-five women with TNBC and residual invasive disease after standard neoadjuvant chemotherapy were randomized to nivolumab, capecitabine, or the combination. Here we show that a combination of nivolumab plus capecitabine leads to a greater increase in PIS from baseline to week 6 (91%) compared with nivolumab (47%) or capecitabine (53%) alone (log-rank p?=?0.08), meeting the pre-specified primary endpoint. In addition, the presence of circulating tumor DNA (ctDNA) is associated with disease recurrence, with no new safety signals in the combination arm. Our results provide efficacy and safety data on this combination in TNBC and support further development of PIS and ctDNA analyses to identify patients at high risk of recurrence.
Nature Communications
Comprehensive Mutational Scanning of EGFR Reveals TKI Sensitivities of Extracellular Domain Mutants
Hayes TK, Aquilanti E, Persky NS, Yang X, Kim EE, Brenan L, Goodale AB, Alan D, Sharpe T, Shue RE, Westlake L, Golomb L, Silverman BR, Morris MD, Fisher TR, Beyene E, Li YY, Cherniack AD, Piccioni F, Chi AS, Cahill DP, Dietrich J, Batchelor TT, Root DE, Johannessen CM, Meyerson M
The epidermal growth factor receptor, EGFR, is frequently activated in lung cancer and glioblastoma by genomic alterations including missense mutations. The different mutation spectra in these diseases are reflected in divergent responses to EGFR inhibition: significant patient benefit in lung cancer, but limited in glioblastoma. Here, we report a comprehensive mutational analysis of EGFR function. We perform saturation mutagenesis of EGFR and assess function of ~22,500 variants in a human EGFR-dependent lung cancer cell line. This approach reveals enrichment of erlotinib-insensitive variants of known and unknown significance in the dimerization, transmembrane, and kinase domains. Multiple EGFR extracellular domain variants, not associated with approved targeted therapies, are sensitive to afatinib and dacomitinib in vitro. Two glioblastoma patients with somatic EGFR G598V dimerization domain mutations show responses to dacomitinib treatment followed by within-pathway resistance mutation in one case. In summary, this comprehensive screen expands the landscape of functional EGFR variants and suggests broader clinical investigation of EGFR inhibition for cancers harboring extracellular domain mutations.
Nature Communications
Gómez Tejeda Zañudo J, Barroso-Sousa R, Jain E, Jin Q, Li T, Buendia-Buendia JE, Pereslete A, Abravanel DL, Ferreira AR, Wrabel E, Helvie K, Hughes ME, Partridge AH, Overmoyer B, Lin NU, Tayob N, Tolaney SM, Wagle N
The landscape of cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) resistance is still being elucidated and the optimal subsequent therapy to overcome resistance remains uncertain. Here we present the final results of a phase Ib/IIa, open-label trial (NCT02871791) of exemestane plus everolimus and palbociclib for CDK4/6i-resistant metastatic breast cancer. The primary objective of phase Ib was to evaluate safety and tolerability and determine the maximum tolerated dose/recommended phase II dose (100?mg palbociclib, 5?mg everolimus, 25?mg exemestane). The primary objective of phase IIa was to determine the clinical benefit rate (18.8%, n?=?6/32), which did not meet the predefined endpoint (65%). Secondary objectives included pharmacokinetic profiling (phase Ib), objective response rate, disease control rate, duration of response, and progression free survival (phase IIa), and correlative multi-omics analysis to investigate biomarkers of resistance to CDK4/6i. All participants were female. Multi-omics data from the phase IIa patients (n?=?24 tumor/17 blood biopsy exomes; n?=?27 tumor transcriptomes) showed potential mechanisms of resistance (convergent evolution of HER2 activation, BRAFV600E), identified joint genomic/transcriptomic resistance features (ESR1 mutations, high estrogen receptor pathway activity, and a Luminal A/B subtype; ERBB2/BRAF mutations, high RTK/MAPK pathway activity, and a HER2-E subtype), and provided hypothesis-generating results suggesting that mTOR pathway activation correlates with response to the trial's therapy. Our results illustrate how genome and transcriptome sequencing may help better identify patients likely to respond to CDK4/6i therapies.
American Journal of Neuroradiology
Guenette JP, Qin L
Antibodies
O'Neill AF, Nguyen EM, Maldonado ED, Chang MR, Sun J, Zhu Q, Marasco WA
Antioxidants and Redox Signaling
Cifric S, Folino P, Clericuzio C, Maciel T, Anderson KC
Blood Advances
Cardiovascular Events Reported in Patients with B-Cell Malignancies Treated with Zanubrutinib
Brown JR
BMJ
Gupta S, Chen KL, Devaraj N, Wells SL, Seitter RH, Kaunfer SA, Jose AM, Rao SP, Ortega JL, Green-Lingren O, Hayden R, Bendapudi PK, Chute DF, Sise ME, Motwani SS, Xu W, Sehgal K, Reynolds KL, Leaf DE
British Journal of Haematology
Richardson PG
Cancer Immunology Research
Choudhury AD, Kwak L, Yang DD, Kilar JM, Flynn M, Reichel R, Pace AF, Van Allen EM, Kilbridge K, Wei XX, McGregor BA, Pomerantz MM, Bhatt RS, Bubley GJ, Jacene HA, Taplin ME, Harshman LC
Cell Reports Medicine
Prutsch N, He S, Berezovskaya A, Dharia NV, Stegmaier K, Look AT, Zimmerman MW
European Urology
Zhou Y, D'Andrea VD, Shanmugam SP, Stelter I, Stormoen DR, Chroneos R, Hanlon T, Epstein I, Bekele RT, Anderson WJ, Carvalho FFL, Bellmunt J, Mouw KW
Evidence Based Nursing
Mack JW
Journal of Palliative Medicine
Rosenberg AR
Journal of the American Chemical Society
Branching Crisscross Polymerization of Single-Stranded DNA Slats
Deng J, Minev D, Ershova A, Shih WM
JAMA Otolaryngology – Head and Neck Surgery
Neoadjuvant-Intent Immunotherapy in Advanced, Resectable Cutaneous Squamous Cell Carcinoma
Kim EY, Ruiz ES, DeSimone MS, Shalhout SZ, Hanna GJ, Miller DM, Schmults C, Rettig EM, Foreman RK, Sethi R, Thakuria M, Silk AW
Leukemia
Shimony S, Garcia JS, Keating J, Chen EC, Luskin MR, Stahl M, Neuberg DS, DeAngelo DJ, Stone RM, Lindsley RC
Molecular Cancer
Affinity Fine-Tuning Anti-CAIX CAR-T Cells Mitigate On-Target Off-Tumor Side Effects
Wang Y, Buck A, Piel B, Zerefa L, Murugan N, Coherd CD, Huang K, Ficial M, Laimon YN, Signoretti S, Kastrunes GM, Grimaud M, Fayed A, Yuan HC, Nguyen QD, Thai T, Ivanova EV, Paweletz CP, Wu MR, Choueiri TK, Wee JO, Freeman GJ, Barbie DA, Marasco WA
Pediatric Blood and Cancer
Bourgeois W, Yang E, Chiarle R, Burns M
Supportive Care in Cancer
Shin J
