View Archive Newsletters
January 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.
Annals of Oncology
Should Ki-67 be Adopted to Select Breast Cancer Patients for Treatment with Adjuvant Abemaciclib?
Tarantino P, Burstein HJ, Lin NU, Krop IE, Winer EP, Schnitt SJ, Tolaney SM
On October 12, 2021, the U.S. Food and Drug Administration (FDA) approved the cyclin-dependent kinase 4 and 6 (CDK4/6)-inhibitor abemaciclib for the adjuvant treatment of hormone receptor positive (HR+)/HER2-negative (hereafter defined HR+) breast cancer, making abemaciclib the first CDK4/6 inhibitor approved in the early-stage setting and the first new drug approval for the adjuvant treatment of HR+ disease in nearly two decades. This approval was granted based on the results of the monarchE trial, where patients who were randomized to receive adjuvant abemaciclib in addition to endocrine treatment achieved a statistically significant and clinically meaningful improvement in invasive disease-free survival (iDFS).
Measurable Residual Disease Does Not Preclude Prolonged Progression-Free Survival in CLL Treated with Ibrutinib
Wang XV, Stone R
E1912 was a randomized phase 3 trial comparing indefinite ibrutinib plus 6 cycles of rituximab (IR) to 6 cycles of fludarabine, cyclophosphamide, and rituximab (FCR) in untreated younger patients with CLL. We describe measurable residual disease (MRD) levels in E1912 over time and correlate them with clinical outcome. Undetectable MRD rates ( < 1 CLL cell per 104 leukocytes) were 29.1%, 30.3%, 23.4%, and 8.6% at 3, 12, 24, and 36 months for FCR, and significantly lower at 7.9%, 4.2%, and 3.7% at 12, 24, and 36 months for IR, respectively. Undetectable MRD at 3, 12, 24, and 36 months was associated with longer progression-free survival (PFS) in the FCR arm, with hazard ratios (MRD detectable/MRD undetectable) of 4.29 (95% confidence interval [CI], 1.89-9.71), 3.91 (95% CI, 1.39-11.03), 14.12 (95% CI, 1.78-111.73), and not estimable (no events among those with undetectable MRD), respectively. In the IR arm, patients with detectable MRD did not have significantly worse PFS compared with those in whom MRD was undetectable; however, PFS was longer in those with MRD levels
Overcoming IMiD Resistance in T-cell Lymphomas Through Potent Degradation of ZFP91 and IKZF1
Wu W, Nelson G, Donovan KA, Nowak RP, Heavican-Foral TB, Nirmal AJ, Liu H, Yang L, Duffy J, Powers F, Stevenson KE, Jones M, Ng SY, Wu G, Jain S, Xu R, Amaka S, Trevisani C, Donaldson N, Fischer ES, Adelman K, Weinstock DM
Immunomodulatory (IMiD) agents like lenalidomide and pomalidomide induce the recruitment of IKZF1 and other targets to the CRL4CRBN E3 ubiquitin ligase, resulting in their ubiquitination and degradation. These agents are highly active in B-cell lymphomas and a subset of myeloid diseases but have compromised effects in T-cell lymphomas (TCLs). Here we show that two factors determine resistance to IMiDs among TCLs. First, limited CRBN expression reduces IMiD activity in TCLs but can be overcome by newer-generation degrader CC-92480. Using mass spectrometry, we show that CC-92480 selectively degrades IKZF1 and ZFP91 in TCL cells with greater potency than pomalidomide. As a result, CC-92480 is highly active against multiple TCL subtypes and showed greater efficacy than pomalidomide across 4 in vivo TCL models. Second, we demonstrate that ZFP91 functions as a bona fide transcription factor that co-regulates cell survival with IKZF1 in IMiD-resistant TCLs. By activating keynote genes from WNT, NF-kB, and MAP kinase signaling, ZFP91 directly promotes resistance to IKZF1 loss. Moreover, lenalidomide-sensitive TCLs can acquire stable resistance via ZFP91 rewiring, which involves casein kinase 2 (CK2) mediated c-Jun inactivation. Overall, these findings identify a critical transcription factor network within TCLs and provide clinical proof of concept for the novel therapy using next-generation degraders.
Understanding CLL Biology Through Mouse Models of Human Genetics
Ten Hacken E, Wu CJ
Rapid advances in large-scale next-generation sequencing studies of human samples have progressively defined the highly heterogeneous genetic landscape of chronic lymphocytic leukemia (CLL). At the same time, the numerous challenges posed by the difficulties in rapid manipulation of primary B cells and the paucity of CLL cell lines have limited the ability to interrogate the function of the discovered putative disease "drivers," defined in human sequencing studies through statistical inference. Mouse models represent a powerful tool to study mechanisms of normal and malignant B-cell biology and for preclinical testing of novel therapeutics. Advances in genetic engineering technologies, including the introduction of conditional knockin/knockout strategies, have opened new opportunities to model genetic lesions in a B-cell-restricted context. These new studies build on the experience of generating the MDR mice, the first example of a genetically faithful CLL model, which recapitulates the most common genomic aberration of human CLL: del(13q). In this review, we describe the application of mouse models to the studies of CLL pathogenesis and disease transformation from an indolent to a high-grade malignancy (ie, Richter syndrome [RS]) and treatment, with a focus on newly developed genetically inspired mouse lines modeling recurrent CLL genetic events. We discuss how these novel mouse models, analyzed using new genomic technologies, allow the dissection of mechanisms of disease evolution and response to therapy with greater depth than previously possible and provide important insight into human CLL and RS pathogenesis and therapeutic vulnerabilities. These models thereby provide valuable platforms for functional genomic analyses and treatment studies.
Functional Precision Oncology: Testing Tumors with Drugs to Identify Vulnerabilities and Novel Combinations
Letai A, Bhola P
Functional precision medicine is a strategy whereby live tumor cells from affected individuals are directly perturbed with drugs to provide immediately translatable, personalized information to guide therapy. The heterogeneity of human cancer has led to the realization that personalized approaches are needed to improve treatment outcomes. Precision oncology has traditionally used static features of the tumor to dictate which therapies should be used. Static features can include expression of key targets or genomic analysis of mutations to identify therapeutically targetable "drivers." Although a surprisingly small proportion of individuals derive clinical benefit from the static approach, functional precision medicine can provide additional information regarding tumor vulnerabilities. We discuss emerging technologies for functional precision medicine as well as limitations and challenges in using these assays in the clinical trials that will be necessary to determine whether functional precision medicine can improve outcomes and eventually become a standard tool in clinical oncology.
Journal of Clinical Oncology
Adjuvant Therapy for Stage II Colon Cancer: ASCO Guideline Update
PURPOSE: To develop recommendations for adjuvant therapy for patients with resected stage II colon cancer.
METHODS: ASCO convened an Expert Panel to conduct a systematic review of relevant studies and develop recommendations for clinical practice.
RESULTS: Twenty-one observational studies and six randomized controlled trials met the systematic review inclusion criteria.
RECOMMENDATIONS: Adjuvant chemotherapy (ACT) is not routinely recommended for patients with stage II colon cancer who are not in a high-risk subgroup. Patients with T4 tumors are at higher risk of recurrence and should be offered ACT, whereas patients with other high-risk factors, including sampling of fewer than 12 lymph nodes in the surgical specimen, perineural or lymphatic invasion, poorly or undifferentiated tumor grade, intestinal obstruction, tumor perforation, or grade BD3 tumor budding, may be offered ACT. The addition of oxaliplatin to fluoropyrimidine-based ACT is not routinely recommended, but may be offered as a result of shared decision making. Patients with mismatch repair deficiency/microsatellite instability tumors should not be routinely offered ACT; if the combination of mismatch repair deficiency/microsatellite instability and high-risk factors results in a decision to offer ACT, oxaliplatin-containing chemotherapy is recommended. Duration of oxaliplatin-containing chemotherapy is also addressed, with recommendations for 3 or 6 months of treatment with capecitabine and oxaliplatin or fluorouracil, leucovorin, and oxaliplatin, with decision making informed by key evidence of 5-year disease-free survival in each treatment subgroup and the rate of adverse events, including peripheral neuropathy. Additional information is available at www.asco.org/gastrointestinal-cancer-guidelines.
Journal of Clinical Oncology
Health-Related Quality of Life in Metastatic, Hormone-Sensitive Prostate Cancer: ENZAMET (ANZUP 1304), an International, Randomized Phase III Trial Led by ANZUP
PURPOSE: We previously reported that enzalutamide improved overall survival when added to standard of care in metastatic, hormone-sensitive prostate cancer. Here, we report its effects on aspects of health-related quality of life (HRQL). METHODS: HRQL was assessed with the European Organisation for Research and Treatment of Cancer core quality-of-life questionnaire and QLM-PR25 at weeks 0, 4, 12, and then every 12 weeks until progression. Scores from week 4 to 156 were analyzed with repeated measures modeling to calculate group means and differences. Deterioration-free survival was from random assignment until the earliest of death, clinical progression, discontinuation of study treatment, or a worsening of 10 points or more from baseline in fatigue, physical function, cognitive function, or overall health and quality of life (OHQL). HRQL scores range from 0 (lowest possible) to 100 (highest possible). RESULTS: HRQL was assessed in 1,042 of 1,125 participants (93%). Differences in means favored control over enzalutamide for fatigue (5.2, 95% CI, 3.6 to 6.9; P < .001), cognitive function (4.0, 95% CI, 2.5 to 5.5; P < .001), and physical function (2.6, 95% CI, 1.3 to 3.9; P < .001), but not OHQL (1.2, 95% CI, -0.2 to 2.7; P = .1). Deterioration-free survival rates at 3 years, and log-rank P values comparing the whole distributions, favored enzalutamide over control for OHQL (31% v 17%; P < .0001), cognitive function (31% v 20%; P = .001), and physical function (31% v 22%; P < .001), but not fatigue (24% v 18%; P = .16). The effects of enzalutamide on HRQL were independent of baseline characteristics. CONCLUSION: Enzalutamide was associated with worsening of self-reported fatigue, cognitive function, and physical function, but not OHQL. Enzalutamide was associated with improved deterioration-free survival for OHQL, physical function, and cognitive function because delays in disease progression outweighed early deteriorations in these aspects of HRQL.
Effector-Mediated Membrane Disruption Controls Cell Death in CBASS Antiphage Defense
Duncan-Lowey B, McNamara-Bordewick NK, Kranzusch PJ
Cyclic oligonucleotide-based antiphage signaling systems (CBASS) are antiviral defense operons that protect bacteria from phage replication. Here, we discover a widespread class of CBASS transmembrane (TM) effector proteins that respond to antiviral nucleotide signals and limit phage propagation through direct membrane disruption. Crystal structures of the Yersinia TM effector Cap15 reveal a compact 8-stranded ?-barrel scaffold that forms a cyclic dinucleotide receptor domain that oligomerizes upon activation. We demonstrate that activated Cap15 relocalizes throughout the cell and specifically induces rupture of the inner membrane. Screening for active effectors, we identify the function of distinct families of CBASS TM effectors and demonstrate that cell death via disruption of inner-membrane integrity is a common mechanism of defense. Our results reveal the function of the most prominent class of effector protein in CBASS immunity and define disruption of the inner membrane as a widespread strategy of abortive infection in bacterial phage defense.
Identification of RIOK2 as a Master Regulator of Human Blood Cell Development
Ghosh S, Raundhal M, Myers SA, Carr SA, Petsko GA, Glimcher LH
Anemia is a major comorbidity in aging, chronic kidney and inflammatory diseases, and hematologic malignancies. However, the transcriptomic networks governing hematopoietic differentiation in blood cell development remain incompletely defined. Here we report that the atypical kinase RIOK2 (right open reading frame kinase 2) is a master transcription factor (TF) that not only drives erythroid differentiation, but also simultaneously suppresses megakaryopoiesis and myelopoiesis in primary human stem and progenitor cells. Our study reveals the previously uncharacterized winged helix-turn-helix DNA-binding domain and two transactivation domains of RIOK2 that are critical to regulate key hematopoietic TFs GATA1, GATA2, SPI1, RUNX3 and KLF1. This establishes RIOK2 as an integral component of the transcriptional regulatory network governing human hematopoietic differentiation. Importantly, RIOK2 mRNA expression significantly correlates with these TFs and other hematopoietic genes in myelodysplastic syndromes, acute myeloid leukemia and chronic kidney disease. Further investigation of RIOK2-mediated transcriptional pathways should yield therapeutic approaches to correct defective hematopoiesis in hematologic disorders.
Predictors of Response and Survival in a Large Cohort of 319 Waldenström Macroglobulinemia Patients Treated with Ibrutinib Monotherapy
Castillo JJ, Sarosiek S, Gustine JN, Flynn C, Leventoff C, White TP, Meid KE, Guerrera ML, Kofides A, Liu X, Munshi M, Tsakmaklis N, Hunter ZR, Patterson CJ, Branagan AR, Treon SP
British Journal of Cancer
CDH1 Germline Variants are Enriched in Patients with Colorectal Cancer, Gastric Cancer, and Breast Cancer
Adib E, El Zarif T, Nassar AH, Akl EW, Abou Alaiwi S, Rana HQ, Choueiri TK, Kwiatkowski DJ, Sonpavde G
Cell Chemical Biology
Identification and Validation of Selective Deubiquitinase Inhibitors
Varca AC, Chan WC, Hu B, Magin RS, Roberts RM, Liu X, Zhu H, Seo HS, Dhe-Paganon S, Marto JA, Buhrlage SJ
Genomic Features of Muscle-invasive Bladder Cancer Arising After Prostate Radiotherapy
Mossanen M, Carvalho FLF, Muralidhar V, Preston MA, Reardon B, Conway JR, Curran C, Freeman D, Sonpavde G, Hirsch M, Kibel AS, Van Allen EM, Mouw KW
Genes and Development
Transcription Factor-Mediated Intestinal Metaplasia and the Role of a Shadow Enhancer
Singh H, Seruggia D, Madha S, Saxena M, Nagaraja AK, Wu Z, Zhou J, Huebner AJ, Maglieri A, Hochedlinger K, Orkin SH, Bass AJ, Hornick JL, Shivdasani RA
Head and Neck
Oligometastatic Adenoid Cystic Carcinoma: Correlating Tumor Burden and Time to Treatment with Outcomes
Tyan K, Bae JE, Lorch JH, Margalit DN, Tishler RB, Huynh MA, Jo VY, Haddad RI, Chau NG, Hanna GJ, Schoenfeld JD