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Blood
Targeting MCL-1 and BCL-2: A 1-2 Punch
Brown JR
In this issue of Blood, Thijssen et al report that leukemia or lymphoma cells with TP53 loss have a selective advantage over time when treated with sublethal doses of a BCL-2 or MCL-1 inhibitor, because of reduced activation of BAX and BAK, but this defect can be overcome with dual treatment with both inhibitors. Venetoclax, the first approved drug in the class of BH3-mimetic inhibitors of BCL-2, has emerged as a highly active therapy for both acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL). As a BH3-mimetic itself, venetoclax works by binding to BCL-2 and displacing endogenous proapoptotic BH3-mimetics such as BIM, leading to activation of BAX and BAK to induce apoptosis. This activity of venetoclax is downstream of TP53 function, suggesting that venetoclax-induced cell death could remain highly effective, regardless of TP53 loss, consistent with in vitro data in short-term assays in CLL. This observation is also consistent with initial clinical observations that venetoclax induces deep remission in CLL, with or without TP53, although more recent data show that TP53 loss leads to a shorter duration of response. In AML also, despite the initial response, TP53 mutations have been associated with early acquired resistance, often accompanied by increased allele frequency of the mutation or selection for biallelic loss. These findings suggest that short-term killing with venetoclax may not be substantially affected by TP53 loss, but that, over time, the TP53 mutant clones are likely to have an advantage.
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Blood
The Clinical and Functional Effects of TERT Variants in Myelodysplastic Syndrome
Reilly CR, Myllymäki M, Redd RA, Karunakaran D, Tsai FD, Gibson CJ, Rana HQ, Zhong L, Orr EH, Chen MM, De Vivo I, DeAngelo DJ, Cutler C, Antin JH, Neuberg D, Garber JE, Nandakumar J, Agarwal S, Lindsley RC
Germline pathogenic TERT variants are associated with short telomeres and an increased risk of developing myelodysplastic syndrome (MDS) among patients with a telomere biology disorder. We identified TERT rare variants in 41 of 1514 MDS patients (2.7%) without a clinical diagnosis of a telomere biology disorder who underwent allogeneic transplantation. Patients with a TERT rare variant had shorter telomere length (p<0.001) and younger age at MDS diagnosis (52 vs. 59 years, p=0.03) than patients without a TERT rare variant. In multivariable models, TERT rare variants were associated with inferior overall survival (p=0.034) driven by an increased incidence of non-relapse mortality (NRM) (p=0.015). Death from a non-infectious pulmonary cause was more frequent among patients with a TERT rare variant. The majority of variants were missense substitutions and classified as variants of unknown significance (VUS). Therefore, we cloned all rare missense variants and quantified their impact on telomere elongation in a cell-based assay. We found that 90 percent of TERT rare variants had severe or intermediate impairment in their capacity to elongate telomeres. Using a homology model of human TERT bound to the shelterin protein TPP1, we inferred that TERT rare variants disrupt domain-specific functions, including catalysis, protein-RNA interactions, and recruitment to telomeres. Our results indicate that the contribution of TERT rare variants to MDS pathogenesis and NRM risk is underrecognized. Routine screening for TERT rare variants in MDS patients regardless of age or clinical suspicion may identify clinically inapparent telomere biology disorders and improve transplant outcomes through risk-adapted approaches.
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Journal of Clinical Oncology
Updated Standardized Definitions for Efficacy End Points (STEEP) in Adjuvant Breast Cancer Clinical Trials: STEEP Version 2.0
Tolaney SM, Frank E, Tung NM, Winer EP
PURPOSE: The Standardized Definitions for Efficacy End Points (STEEP) criteria, established in 2007, provide standardized definitions of adjuvant breast cancer clinical trial end points. Given the evolution of breast cancer clinical trials and improvements in outcomes, a panel of experts reviewed the STEEP criteria to determine whether modifications are needed.
METHODS: We conducted systematic searches of ClinicalTrials.gov for adjuvant systemic and local-regional therapy trials for breast cancer to investigate if the primary end points reported met STEEP criteria. On the basis of common STEEP deviations, we performed a series of simulations to evaluate the effect of excluding non-breast cancer deaths and new nonbreast primary cancers from the invasive disease-free survival end point.
RESULTS: Among 11 phase III breast cancer trials with primary efficacy end points, three had primary end points that followed STEEP criteria, four used STEEP definitions but not the corresponding end point names, and four used end points that were not included in the original STEEP manuscript. Simulation modeling demonstrated that inclusion of second nonbreast primary cancer can increase the probability of incorrect inferences, can decrease power to detect clinically relevant efficacy effects, and may mask differences in recurrence rates, especially when recurrence rates are low.
CONCLUSION: We recommend an additional end point, invasive breast cancer-free survival, which includes all invasive disease-free survival events except second nonbreast primary cancers. This end point should be considered for trials in which the toxicities of agents are well-known and where the risk of second primary cancer is small. Additionally, we provide end point recommendations for local therapy trials, low-risk populations, noninferiority trials, and trials incorporating patient-reported outcomes.
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Journal of the National Cancer Institute
Expanding Criteria for Prognostic Stage IA in Hormone Receptor-Positive Breast Cancer
Kantor O, King TA, Burstein HJ, Winer EP, Dey T, Mittendorf EA
BACKGROUND: The prognostic significance of patients with low-risk Recurrence Score (RS) results in the context of the American Joint Committee on Cancer (AJCC) 8th-edition pathologic prognostic staging has not been investigated. We evaluated if expanded RS criteria can be considered for downstaging in AJCC pathologic prognostic staging.
METHODS: Using Surveillance, Epidemiology, and End Results data we identified patients with T1-3N0-3M0 HR-positive/HER2-negative breast cancer treated from 2010-2015 with follow-up data through 2016. We evaluated TNM categories, grade, and RS result. The primary outcome measured was 5-year disease-specific survival (DSS) of patients with low-risk RS results not already pathologic prognostic stage IA, determined by T and N categories per AJCC 8th edition. All statistical tests were 2-sided.
RESULTS: Of 154,050 patients with median follow-up of 49 months (range = 0-83), RS results were obtained in 60,886 (39.5%): RS was .05). For those with RS 18-25, there was a small decrease in DSS for T2N0 (2.3%) and modest decrease for T1-2N1 (4.2%-6.4%) compared to pathologic prognostic stage IA patients (P<.001).
CONCLUSION: Patients with RS
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JAMA
US Preventive Services Task Force Recommendations for Colorectal Cancer Screening: Forty-Five Is the New Fifty
Ng K, Schrag D
Colorectal cancer is the third most common cause of cancer in men and women in the US and the second leading cause of cancer death in the US when men and women are combined. However, colorectal cancer is one of the most preventable malignancies, with a long natural history of progression from a preneoplastic to neoplastic state and the availability of effective screening tests that can detect disease early. Diet and lifestyle factors are strongly linked to both the incidence and mortality of colorectal cancer, and studies suggest that the risk of colorectal cancer could be reduced with diet and lifestyle modification.
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JAMA Oncology
Accompanying Patients in the Time of COVID-19
Jacobson JO
On a late autumn afternoon early in the second wave of the COVID-19 pandemic, I found myself masked and eye-shielded in a darkened, crowded room on our inpatient palliative care service. Karen, a woman in her 60s, was lying in bed trying to find a position to reduce the pressure on her back where recurrent lung cancer was attacking her chest wall. She managed her patient-controlled analgesia carefully; she wanted to be alert for this moment. I stood with the palliative care attending physician at the foot of the bed in the tiny room. The social worker and another palliative care practitioner held up 2 iPads and a cell phone. Faces familiar to the patient—her husband, daughter, and closest friend—filled the screens. There were no more options left for treating Karen’s horrific cancer, and we were there to clarify her preferences for further care.
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Nature Chemical Biology
Acute Pharmacological Degradation of Helios Destabilizes Regulatory T Cells
Wang ES, Verano AL, Nowak RP, Yuan JC, Donovan KA, Eleuteri NA, Yue H, Ngo KH, Lizotte PH, Gokhale PC, Gray NS, Fischer ES
The zinc-finger transcription factor Helios is critical for maintaining the identity, anergic phenotype and suppressive activity of regulatory T (Treg) cells. While it is an attractive target to enhance the efficacy of currently approved immunotherapies, no existing approaches can directly modulate Helios activity or abundance. Here, we report the structure-guided development of small molecules that recruit the E3 ubiquitin ligase substrate receptor cereblon to Helios, thereby promoting its degradation. Pharmacological Helios degradation destabilized the anergic phenotype and reduced the suppressive activity of Treg cells, establishing a route towards Helios-targeting therapeutics. More generally, this study provides a framework for the development of small-molecule degraders for previously unligandable targets by reprogramming E3 ligase substrate specificity.
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Science Translational Medicine
cIAP1/2 Antagonism Eliminates MHC Class I-Negative Tumors Through T Cell-Dependent Reprogramming of Mononuclear Phagocytes
Roehle K, Qiang L, Ventre KS, Heid D, Ali LR, Lenehan P, Heckler M, Crowley SJ, Stump CT, Ro G, Godicelj A, Bhuiyan AM, Yang A, Quiles Del Rey M, Biary T, Luoma AM, Bruck PT, Tegethoff JF, Nopper SL, Wucherpfennig KW, Mancias JD, Agudo J, Dougan M, Dougan SK
Loss of major histocompatibility complex (MHC) class I and interferon-g (IFN-g) sensing are major causes of primary and acquired resistance to checkpoint blockade immunotherapy. Thus, additional treatment options are needed for tumors that lose expression of MHC class I. The cellular inhibitor of apoptosis proteins 1 and 2 (cIAP1/2) regulate classical and alternative nuclear factor kB (NF-kB) signaling. Induction of noncanonical NF-kB signaling with cIAP1/2 antagonists mimics costimulatory signaling, augmenting antitumor immunity. We show that induction of noncanonical NF-kB signaling induces T cell-dependent immune responses, even in b2-microglobulin (b2M)-deficient tumors, demonstrating that direct CD8 T cell recognition of tumor cell-expressed MHC class I is not required. Instead, T cell-produced lymphotoxin reprograms both mouse and human macrophages to be tumoricidal. In wild-type mice, but not mice incapable of antigen-specific T cell responses, cIAP1/2 antagonism reduces tumor burden by increasing phagocytosis of live tumor cells. Efficacy is augmented by combination with CD47 blockade. Thus, activation of noncanonical NF-kB stimulates a T cell-macrophage axis that curtails growth of tumors that are resistant to checkpoint blockade because of loss of MHC class I or IFN-g sensing. These findings provide a potential mechanism for controlling checkpoint blockade refractory tumors.
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Communications Biology
Integrated Genomics and Comprehensive Validation Reveal Drivers of Genomic Evolution in Esophageal Adenocarcinoma
Kumar S, Buon L, Talluri S, Roncador M, Liao C, Zhao J, Shi J, Chakraborty C, Gonzalez G, Tai YT, Prabhala R, Samur MK, Munshi NC, Shammas MA
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Neuro-Oncology
Activity of PD-1 Blockade with Nivolumab Among Patients with Recurrent Atypical/Anaplastic Meningioma: Phase II Trial Results
Bi WL, Nayak L, Meredith DM, Driver J, Hoffman S, Li Y, Lee EQ, Beroukhim R, Rinne M,
McFaline-Figueroa R, Chukwueke U, McCluskey C, Gaffey S, Cherniack AD, Stefanik J, Doherty L, Taubert C, Cifrino M, LaFrankie D, Graillon T, Wen PY, Ligon KL, Al-Mefty O, Huang RY,
Muzikansky A, Chiocca EA, Santagata S, Reardon DA
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