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.
November 15, 2021
Phase 1 Study of Ibrutinib and the CXCR4 Antagonist Ulocuplumab in CXCR4-Mutated Waldenström Macroglobulinemia
Treon SP, Meid K, Hunter ZR, Flynn CA, Sarosiek SR, Leventoff CR, White TP, Cao Y, Demos MG, Guerrera ML, Kofides A, Liu X, Xu L, Patterson CJ, Munshi M, Tsakmaklis N, Yang G, Ghobrial IM, Branagan AR, Castillo JJ
MYD88 and CXCR4 mutations are common in Waldenström macroglobulinemia (WM). Mutated CXCR4 (CXCR4Mut) impacts BTK-inhibitor response. We conducted a phase 1 trial of the CXCR4-antagonist ulocuplumab with ibrutinib in this first-ever study to target CXCR4Mut in WM. Ibrutinib was initiated at 420 mg/d with cycle 1 and continued until intolerance or progression; ulocuplumab was given cycles 1 to 6, with a 3 + 3 dose-escalation design. Each cycle was 4 weeks. Thirteen symptomatic patients, of whom 9 were treatment-naive patients were enrolled. Twelve were evaluable for response. At best response, their median serum immunoglobulin M declined from 5574 to 1114 mg/dL; bone marrow disease decreased from 65% to 10%, and hemoglobin increased from 10.1 to 14.2 g/dL (P < .001). The major and VGPR response rates were 100% and 33%, respectively, with VGPRs observed at lower ulocuplumab dose cohorts. Median times to minor and major responses were 0.9 and 1.2 months, respectively. With a median follow-up of 22.4 months, the estimated 2-year progression-free survival was 90%. The most frequent recurring grade 2 adverse events included reversible thrombocytopenia, rash, and skin infections. Ulocuplumab dose-escalation did not impact adverse events. The study demonstrates the feasibility of combining a CXCR4-antagonist with ibrutinib and provides support for the development of CXCR4-antagonists for CXCR4Mut WM. This trial was registered at www.clinicaltrials.gov as #NCT03225716.
Journal of Clinical Oncology
Amivantamab: Treating EGFR Exon 20-Mutant Cancers with Bispecific Antibody-Mediated Receptor Degradation
Köhler J, Jänne PA
Insertions in exon 20 of the epidermal growth factor (EGF) receptor (EGFR Ex20ins) represent the third most common type of activating EGFR mutations in non–small-cell lung cancer (NSCLC). With some geographical variation, they are detected in up to 4% of all advanced NSCLC and in 4%-12% of EGFR mutation–positive NSCLC. EGFR Ex20ins are more common in tumors among never smokers, but unlike common Exon19 deletions or Exon21 L858R point mutations, most of the Ex20ins mutations (except for EGFR A763_Y764FQEA) exhibit de novo resistance to the currently approved first-line EGFR tyrosine kinase inhibitors (TKIs): erlotinib, gefitinib, afatinib, and osimertinib. Therefore, chemotherapy represents the mainstay treatment option. Mechanisms of TKI resistance are multifactorial including steric hindrance, similar TKI affinities to Exon20ins-mutant EGFR, and unchanged ATP binding of mutant compared with wild-type EGFR.
Journal of Clinical Oncology
Biologic Assignment Trial of Reduced-Intensity Hematopoietic Cell Transplantation Based on Donor Availability in Patients 50-75 Years of Age with Advanced Myelodysplastic Syndrome
PURPOSE: Allogeneic hematopoietic cell transplantation (HCT) is the only potentially curative therapy for myelodysplastic syndromes (MDS), although it is infrequently offered to older patients. The relative benefits of HCT over non-HCT therapy in older patients with higher-risk MDS have not been defined.
METHODS: We conducted a multicenter biologic assignment trial comparing reduced-intensity HCT to hypomethylating therapy or best supportive care in subjects 50-75 years of age with intermediate-2 or high-risk de novo MDS. The primary outcome was overall survival probability at 3 years. Between January 2014 and November 2018, we enrolled 384 subjects at 34 centers. Subjects were assigned to the Donor or No-Donor arms according to the availability of a matched donor within 90 days of study registration.
RESULTS: The median follow-up time for surviving subjects was 34.2 months (range: 2.3-38 months) in the Donor arm and 26.9 months (range: 2.4-37.2 months) in the No-Donor arm. In an intention-to-treat analysis, the adjusted overall survival rate at 3 years in the Donor arm was 47.9% (95% CI, 41.3 to 54.1) compared with 26.6% (95% CI, 18.4 to 35.6) in the No-Donor arm (P = .0001) with an absolute difference of 21.3% (95% CI, 10.2 to 31.8). Leukemia-free survival at 3 years was greater in the Donor arm (35.8%; 95% CI, 29.8 to 41.8) compared with the No-Donor arm (20.6%; 95% CI, 13.3 to 29.1; P = .003). The survival benefit was seen across all subgroups examined.
CONCLUSION: We observed a significant survival advantage in older subjects with higher-risk MDS who have a matched donor identified and underwent reduced-intensity HCT, when compared with those without a donor. HCT should be included as an integral part of MDS management plans in fit older adults with higher-risk MDS
Clinical Activity and Safety of Cabozantinib for Brain Metastases in Patients with Renal Cell Carcinoma
Hirsch L, Martinez Chanza N, Farah S, Xie W, Braun DA, Xu W, Varkaris A, Brastianos PK, Krajewski KM, Harshman LC, Choueiri TK
IMPORTANCE: Patients with brain metastases from renal cell carcinoma (RCC) have been underrepresented in clinical trials, and effective systemic therapy is lacking. Cabozantinib shows robust clinical activity in metastatic RCC, but its effect on brain metastases remains unclear.
OBJECTIVE: To assess the clinical activity and toxic effects of cabozantinib to treat brain metastases in patients with metastatic RCC.
DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study included patients with metastatic RCC and brain metastases treated in 15 international institutions (US, Belgium, France, and Spain) between January 2014 and October 2020. Cohort A comprised patients with progressing brain metastases without concomitant brain-directed local therapy, and cohort B comprised patients with stable or progressing brain metastases concomitantly treated by brain-directed local therapy.
EXPOSURES: Receipt of cabozantinib monotherapy at any line of treatment.
MAIN OUTCOMES AND MEASURES: Intracranial radiological response rate by modified Response Evaluation Criteria in Solid Tumors, version 1.1, and toxic effects of cabozantinib.
RESULTS: Of the 88 patients with brain metastases from RCC included in the study, 33 (38%) were in cohort A and 55 (62%) were in cohort B; the majority of patients were men (n = 69; 78%), and the median age at cabozantinib initiation was 61 years (range, 34-81 years). Median follow-up was 17 months (range, 2-74 months). The intracranial response rate was 55% (95% CI, 36%-73%) and 47% (95% CI, 33%-61%) in cohorts A and B, respectively. In cohort A, the extracranial response rate was 48% (95% CI, 31%-66%), median time to treatment failure was 8.9 months (95% CI, 5.9-12.3 months), and median overall survival was 15 months (95% CI, 9.0-30.0 months). In cohort B, the extracranial response rate was 38% (95% CI, 25%-52%), time to treatment failure was 9.7 months (95% CI, 6.0-13.2 months), and median overall survival was 16 months (95% CI, 12.0-21.9 months). Cabozantinib was well tolerated, with no unexpected toxic effects or neurological adverse events reported. No treatment-related deaths were observed.
CONCLUSIONS AND RELEVANCE: In this cohort study, cabozantinib showed considerable intracranial activity and an acceptable safety profile in patients with RCC and brain metastases. Support of prospective studies evaluating the efficacy of cabozantinib for brain metastases in patients with RCC is critical.
Low Glycaemic Diets Alter Lipid Metabolism to Influence Tumour Growth
Zhang Y, Yuan C, Wolpin BM, Vander Heiden MG
Dietary interventions can change metabolite levels in the tumour microenvironment, which might then affect cancer cell metabolism to alter tumour growth1-5. Although caloric restriction (CR) and a ketogenic diet (KD) are often thought to limit tumour progression by lowering blood glucose and insulin levels6-8, we found that only CR inhibits the growth of select tumour allografts in mice, suggesting that other mechanisms contribute to tumour growth inhibition. A change in nutrient availability observed with CR, but not with KD, is lower lipid levels in the plasma and tumours. Upregulation of stearoyl-CoA desaturase (SCD), which synthesises monounsaturated fatty acids, is required for cancer cells to proliferate in a lipid-depleted environment, and CR also impairs tumour SCD activity to cause an imbalance between unsaturated and saturated fatty acids to slow tumour growth. Enforcing cancer cell SCD expression or raising circulating lipid levels through a higher-fat CR diet confers resistance to the effects of CR. By contrast, although KD also impairs tumour SCD activity, KD-driven increases in lipid availability maintain the unsaturated to saturated fatty acid ratios in tumours, and changing the KD fat composition to increase tumour saturated fatty acid levels cooperates with decreased tumour SCD activity to slow tumour growth. These data suggest that diet-induced mismatches between tumour fatty acid desaturation activity and the availability of specific fatty acid species determine whether low glycaemic diets impair tumour growth.
Nature Cell Biology
Dynamic Transcriptional Reprogramming Leads to Immunotherapeutic Vulnerabilities in Myeloma
Frede J, Anand P, Sotudeh N, Pinto RA, Nair MS, Stuart H, Yee AJ, Vijaykumar T, Waldschmidt JM, Potdar S, Kloeber JA, Kokkalis A, Dimitrova V, Mann M, Laubach JP, Richardson PG, Anderson KC, Raje NS, Knoechel B, Lohr JG
While there is extensive evidence for genetic variation as a basis for treatment resistance, other sources of variation result from cellular plasticity. Using multiple myeloma as an example of an incurable lymphoid malignancy, we show how cancer cells modulate lineage restriction, adapt their enhancer usage and employ cell-intrinsic diversity for survival and treatment escape. By using single-cell transcriptome and chromatin accessibility profiling, we show that distinct transcriptional states co-exist in individual cancer cells and that differential transcriptional regulon usage and enhancer rewiring underlie these alternative transcriptional states. We demonstrate that exposure to standard treatment further promotes transcriptional reprogramming and differential enhancer recruitment while simultaneously reducing developmental potential. Importantly, treatment generates a distinct complement of actionable immunotherapy targets, such as CXCR4, which can be exploited to overcome treatment resistance. Our studies therefore delineate how to transform the cellular plasticity that underlies drug resistance into immuno-oncologic therapeutic opportunities.
Inner Nuclear Protein Matrin-3 Coordinates Cell Differentiation by Stabilizing Chromatin Architecture
Cha HJ, Kai Y, Liu T, Zhu Q, Tothova Z, Orkin SH
Precise control of gene expression during differentiation relies on the interplay of chromatin and nuclear structure. Despite an established contribution of nuclear membrane proteins to developmental gene regulation, little is known regarding the role of inner nuclear proteins. Here we demonstrate that loss of the nuclear scaffolding protein Matrin-3 (Matr3) in erythroid cells leads to morphological and gene expression changes characteristic of accelerated maturation, as well as broad alterations in chromatin organization similar to those accompanying differentiation. Matr3 protein interacts with CTCF and the cohesin complex, and its loss perturbs their occupancy at a subset of sites. Destabilization of CTCF and cohesin binding correlates with altered transcription and accelerated differentiation. This association is conserved in embryonic stem cells. Our findings indicate Matr3 negatively affects cell fate transitions and demonstrate that a critical inner nuclear protein impacts occupancy of architectural factors, culminating in broad effects on chromatin organization and cell differentiation.
Esophageal Cancer Mutational Signatures Around the World
Mutational signatures can shed light onto mechanisms of carcinogenesis and reveal the mutagenic impact of novel and established environmental risk factors. A new study examines the mutational spectra of esophageal squamous cell cancer together with exposure information in regions of high and low incidence of the disease, and demonstrates both the limitations and potential of mutational signature analyses.
Distinction of Lymphoid and Myeloid Clonal Hematopoiesis
Niroula A, Sekar A, Murakami MA, Trinder M, Agrawal M, Wong WJ, Bick AG, Uddin MM, Gibson CJ, Griffin GK, Honigberg MC, Zekavat SM, Paruchuri K, Natarajan P, Ebert BL
Clonal hematopoiesis (CH) results from somatic genomic alterations that drive clonal expansion of blood cells. Somatic gene mutations associated with hematologic malignancies detected in hematopoietic cells of healthy individuals, referred to as CH of indeterminate potential (CHIP), have been associated with myeloid malignancies, while mosaic chromosomal alterations (mCAs) have been associated with lymphoid malignancies. Here, we analyzed CHIP in 55,383 individuals and autosomal mCAs in 420,969 individuals with no history of hematologic malignancies in the UK Biobank and Mass General Brigham Biobank. We distinguished myeloid and lymphoid somatic gene mutations, as well as myeloid and lymphoid mCAs, and found both to be associated with risk of lineage-specific hematologic malignancies. Further, we performed an integrated analysis of somatic alterations with peripheral blood count parameters to stratify the risk of incident myeloid and lymphoid malignancies. These genetic alterations can be readily detected in clinical sequencing panels and used with blood count parameters to identify individuals at high risk of developing hematologic malignancies.
American Journal of Human Genetics
Allele-Specific Epigenetic Activity in Prostate Cancer and Normal Prostate Tissue Implicates Prostate Cancer Risk Mechanisms
Shetty A, Seo JH, Bell CA, O'Connor EP, Pomerantz MM, Freedman ML, Gusev A
PRM-LIVE with Trapped Ion Mobility Spectrometry and Its Application in Selectivity Profiling of Kinase Inhibitors
Zhu H, Ficarro SB, Alexander WM, Fleming LE, Adelmant G, Marto JA
Inference in Response-Adaptive Clinical Trials When the Enrolled Population Varies Over Time
Russo M, Ventz S, Wang V, Trippa L
Defibrotide: Real World Management of Veno-Occlusive Disease/ Sinusoidal Obstructive Syndrome after Stem Cell Transplant
Kim HT, Richardson PG, Soiffer RJ, Antin JH, Cutler CS, Nikiforow S, Gooptu M, Koreth J, Romee R, Ho VT
BMC Public Health
Implementation of an Organizational Intervention to Improve Low-Wage Food Service Workers' Safety, Health and Wellbeing: Findings from the Workplace Organizational Health Study
Sorensen G, Peters SE, Stelson E, Wallace LM, Burke L, Nagler EM, Karapanos M, Wagner GR
British Journal of Haematology
Patient-Reported Outcomes in Relapsed/Refractory Multiple Myeloma Treated with Melflufen Plus Dexamethasone: Analyses from the Phase II HORIZON Study
Laubach J, Nadeem O, Richardson PG
The Treatment Landscape of Metastatic Prostate Cancer
Yamada Y, Beltran H
Activation of Notch and Myc Signaling Via B Cell-Restricted Depletion of Dnmt3a Generates a Consistent Murine Model of Chronic Lymphocytic Leukemia
Biran A, Yin S, Ten Hacken E, Parvin S, Lucas F, Uduman M, Gutierrez C, Dangle N, Billington L, Regis FF, Mohammad A, Hoffmann GB, Stevenson K, Zheng M, Witten E, Fernandes S, Brown JR, Aster JC, Gnirke A, Neuberg DS, Letai A, Carrasco RD, Wu CJ
Cell Chemical Biology
Chemo-Proteomics Exploration of HDAC Degradability by Small Molecule Degraders
Xiong Y, Donovan KA, Eleuteri NA, Kirmani N, Yue H, Razov A, Krupnick NM, Nowak RP, Fischer ES
Clinical Cancer Research
Neoadjuvant and Adjuvant Nivolumab and Lirilumab in Patients with Recurrent, Resectable Squamous Cell Carcinoma of the Head and Neck
Hanna GJ, ONeill A, Shin KY, Wong K, Jo VY, Quinn CT, Cutler JM, Flynn M, Lizotte PH, Annino DJ, Goguen LA, Rettig EM, Sethi RKV, Lorch JH, Schoenfeld JD, Margalit DN, Tishler RB, Desai AM, Cavanaugh ME, Paweletz CP, Egloff AM, Uppaluri R, Haddad RI
Clinical Cancer Research
Real-world Evidence in Support of Oncology Product Registration: A Systematic Review of New Drug Application and Biologics License Application Approvals from 2015-2020
Journal of Adolescent and Young Adult Oncology
The Effect of Pediatric Cancer on Identity in Young Adult Survivors: Results from Project REACH
Chevalier LL, Zwemer EK, Casey R, Recklitis CJ
Journal of Experimental Medicine
Dnmt3a-Mutated Clonal Hematopoiesis Promotes Osteoporosis
Kim PG, Niroula A, Shkolnik V, McConkey M, Lin AE, Slabicki M, Gibson CJ, Griffin G, Sekar A, Brooks DJ, Wong WJ, Cohen DN, Uddin MM, Shin WJ, Pirruccello J, Tsai JM, Agrawal M, Kiel DP, Bouxsein ML, Wein MN, Charles JF, Natarajan P, Ebert BL
Journal of Ovarian Research
Molecular Response to PARP1 Inhibition in Ovarian Cancer Cells as Determined by Mass Spectrometry Based Proteomics
Franz A, Shen C, Charaoui L, Sander C
JCO Oncology Practice
Prostate Cancer Disparities in Risk Group at Presentation and Access to Treatment for Asian Americans, Native Hawaiians, and Pacific Islanders: A Study with Disaggregated Ethnic Groups
Jain B, Muralidhar V, Trinh QD, Nguyen PL, Dee EC
Leukemia and Lymphoma
Targeting Mitochondrial Metabolism in Acute Myeloid Leukemia
Pediatric Blood and Cancer
Anatomic Patterns of Relapse and Progression Following Treatment with (131) I-MIBG in Relapsed or Refractory Neuroblastoma
DuBois SG, Haas-Kogan DA
Disulfiram Use is Associated with Lower Risk of COVID-19: A Retrospective Cohort Study
Fillmore N, Shen C, Nguyen V, La J, Dubreuil M, Strymish J, Brophy M, Wu H, Lieberman J, Do N, Sander C
Radiotherapy and Oncology
Surgical Complications and Clinical Outcomes After Dose-Escalated Trimodality Therapy for Non-Small Cell Lung Cancer in the Era of Intensity-Modulated Radiotherapy
Liu KX, Sierra-Davidson K, Tyan BAK, Orlina LT, Marcoux JP, Kann BH, Kozono D, Mak RH, White A, Singer L
Retinoic Acid Rewires the Adrenergic Core Regulatory Circuitry of Childhood Neuroblastoma
Zimmerman MW, Durbin AD, He S, Oppel F, Shi H, Tao T, Li Z, Berezovskaya A, Look AT
Transplantation and Cellular Therapy
Immune Reconstitution Following High-Dose Chemotherapy and Autologous Stem Cell Transplantation with and without Pembrolizumab Maintenance Therapy in Patients with Lymphoma
Merryman RW, Redd R, Jeter E, McHugh K, Reynolds C, Nazzaro M, Varden A, Brown JR, Crombie JL, Davids MS, Fisher DC, Jacobsen E, Jacobson CA, Kim AI, LaCasce AS, Ng SY, Odejide OO, Parry EM, Joyce RM, Chen YB, Armand P, Ritz J