Welcome to Dana-Farber's Research News
July 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.
Blood
HLH Treatment: Smarter, Not Harder
Henderson LA, Degar BA
In this issue of Blood, Zhang et al present the largest prospective study reported to date demonstrating the clinical benefit of a first-line targeted therapy for children with hemophagocytic lymphohistiocytosis (HLH). HLH is a rare, life-threatening systemic illness that is characterized by unrestrained T-cell activation and cytokine-mediated hyperinflammation, referred to as a cytokine storm. Clinicians are under enormous pressure to act quickly and decisively to interrupt the cycle of immune activation and tissue destruction when faced with a critically ill child with suspected HLH. Although high-dose glucocorticoids coupled with chemotherapy are commonly used, this approach is associated with significant risks. Ruxolitinib has emerged as a promising treatment option in HLH because of its favorable toxicity profile. The study of Zhang and colleagues provides strong support for ruxolitinib as front-line treatment of HLH and represents a major step forward in updating the approach to this life-threatening disease.
Blood
Murdock HM, Kim HT, Tsai HK, Ho VT, Koreth J, Soiffer RJ, Ritz J, Lindsley RC, Gibson CJ
Older patients with acute myeloid leukemia (AML) have high relapse risk and poor survival after allogeneic hematopoietic cell transplantation (HCT). Younger patients may receive myeloablative conditioning to mitigate relapse risk associated with high-risk genetics or measurable residual disease (MRD), but older adults typically receive reduced-intensity conditioning (RIC) to limit toxicity. To identify factors that drive HCT outcomes in older patients, we performed targeted mutational analysis (variant allele fraction 2%) on diagnostic samples from 295 patients with AML aged 60 years who underwent HCT in first complete remission, 91% of whom received RIC, and targeted duplex sequencing at remission in a subset comprising 192 patients. In a multivariable model for leukemia-free survival (LFS) including baseline genetic and clinical variables, we defined patients with low (3-year LFS, 85%), intermediate (55%), high (35%), and very high (7%) risk. Before HCT, 79.7% of patients had persistent baseline mutations, including 18.3% with only DNMT3A or TET2 (DT) mutations and 61.4% with other mutations (MRD positive). In univariable analysis, MRD positivity was associated with increased relapse and inferior LFS, compared with DT and MRD-negative mutations. However, in a multivariable model accounting for baseline risk, MRD positivity had no independent impact on LFS, most likely because of its significant association with diagnostic genetic characteristics, including MDS-associated gene mutations, TP53 mutations, and high-risk karyotype. In summary, molecular associations with MRD positivity and transplant outcomes in older patients with AML are driven primarily by baseline genetics, not by mutations present in remission. In this group of patients, where high-intensity conditioning carries substantial risk of toxicity, alternative approaches to mitigating MRD-associated relapse risk are needed.
Blood
TET2-Mutant Clonal Hematopoiesis and Risk of Gout
Agrawal M, Niroula A, Cunin P, McConkey M, Kovalcik V, Kim PG, Wong WJ, Weeks LD, Lin AE, Miller PG, Gibson CJ, Sekar A, Schaefer IM, Neuberg D, Stone RM, Uddin MM, Griffin GK, Natarajan P, Nigrovic PA, Rao DA, Ebert BL
Gout is a common inflammatory arthritis caused by precipitation of monosodium urate (MSU) crystals in individuals with hyperuricemia. Acute flares are accompanied by secretion of pro-inflammatory cytokines, including interleukin-1 beta (IL-1B). Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related condition predisposing to hematologic cancers and cardiovascular disease. CHIP is associated with elevated IL-1B, thus we investigated CHIP as a risk factor for gout. To test the clinical association between CHIP and gout, we analyzed whole exome sequencing data from 177,824 individuals in the MGB Biobank (MGBB) and UK Biobank (UKB). In both cohorts, the frequency of gout was higher among individuals with CHIP than without CHIP (MGBB, CHIP with variant allele fraction [VAF] 2%: OR, 1.69; 95% CI, 1.09-2.61; P=0.0189; UKB, CHIP with VAF 10%: OR, 1.25; 95% CI, 1.05-1.50; P=0.0133). Moreover, individuals with CHIP and a VAF 10% had an increased risk of incident gout (UKB: HR, 1.28; 95% CI, 1.06-1.55; P=0.0107). In murine models of gout pathogenesis, animals with Tet2 knockout hematopoietic cells had exaggerated IL-1B secretion and paw edema upon administration of MSU crystals. Tet2 knockout macrophages elaborated higher levels of IL-1B in response to MSU crystals in vitro, and this was ameliorated through genetic and pharmacologic Nlrp3 inflammasome inhibition. These studies show that TET2-mutant CHIP is associated with an increased risk of gout in humans and that MSU crystals lead to elevated IL-1B levels in Tet2 knockout murine models. We identify CHIP as an amplifier of NLRP3-dependent inflammatory responses to MSU crystals in gout patients.
Blood
Jutzi JS, Marneth AE, Ciboddo M, Guerra-Moreno A, Kosmidou A, Lozano PR, Doench J, Elf S, Mullally A
Calreticulin (CALR) mutations are frequent, disease-initiating events in myeloproliferative neoplasms (MPN). Although the biological mechanism by which CALR mutations cause MPN has been elucidated, there currently are no clonally selective therapies for CALR-mutant MPN. To identify unique genetic dependencies in CALR-mutant MPN, we performed a whole-genome CRISPR knockout depletion screen in mutant CALR-transformed hematopoietic cells. We found that genes in the N-glycosylation pathway (amongst others) were differentially depleted in mutant CALR-transformed cells as compared with control cells. Using a focused pharmacological in vitro screen targeting unique vulnerabilities uncovered in the CRISPR screen, we found that chemical inhibition of N-glycosylation impaired the growth of mutant CALR-transformed cells, through a reduction in MPL cell surface expression. We treated Calr-mutant knockin mice with the N-glycosylation inhibitor, 2-deoxy-glucose (2-DG), and found a preferential sensitivity of Calr-mutant cells to 2-DG as compared to wild-type cells, and normalization of key MPN disease features. To validate our findings in primary human cells, we performed megakaryocyte colony-forming unit (CFU-MK) assays. We found that N-glycosylation inhibition significantly reduced CFU-MK formation in patient-derived CALR-mutant bone marrow, as compared to bone marrow-derived from healthy donors. In aggregate, our findings advance the development of clonally selective treatments for CALR-mutant MPN.
Cancer Discovery
Santana-Codina N, Quiles Del Rey M, Kapner KS, Zhang H, Gikandi A, Malcolm C, Poupault C, Kuljanin M, John KM, Biancur Lowder KE, Hennessey CJ, Yang A, Nowak JA, Aguirre AJ, Mancias JD
Pancreatic ductal adenocarcinomas (PDAC) depend on autophagy for survival; however, the metabolic substrates that autophagy provides to drive PDAC progression are unclear. Ferritin, the cellular iron storage complex, is targeted for lysosomal degradation (ferritinophagy) by the selective autophagy adaptor NCOA4, resulting in release of iron for cellular utilization. Using patient-derived and murine models of PDAC we now demonstrate that ferritinophagy is upregulated in PDAC to sustain iron availability thereby promoting tumor progression. Quantitative proteomics reveals that ferritinophagy fuels iron-sulfur cluster protein synthesis to support mitochondrial homeostasis. Targeting NCOA4 leads to tumor growth delay and prolonged survival but with development of compensatory iron acquisition pathways. Finally, enhanced ferritinophagy accelerates PDAC tumorigenesis, and an elevated ferritinophagy expression signature predicts for poor prognosis in PDAC patients. Together, our data reveal that maintenance of iron homeostasis is a critical function of PDAC autophagy, and we define NCOA4-mediated ferritinophagy as a therapeutic target in PDAC.
Elife
Integrating Multi-Omics Data Reveals Function and Therapeutic Potential of Deubiquitinating Enzymes
Doherty LM, Mills CE, Boswell SA, Liu X, Hoyt CT, Gyori B, Buhrlage SJ, Sorger PK
Deubiquitinating enzymes (DUBs), ~100 of which are found in human cells, are proteases that remove ubiquitin conjugates from proteins, thereby regulating protein turnover. They are involved in a wide range of cellular activities and are emerging therapeutic targets for cancer and other diseases. Drugs targeting USP1 and USP30 are in clinical development for cancer and kidney disease respectively. However, the majority of substrates and pathways regulated by DUBs remain unknown, impeding efforts to prioritize specific enzymes for research and drug development. To assemble a knowledgebase of DUB activities, co-dependent genes, and substrates, we combined targeted experiments using CRISPR libraries and inhibitors with systematic mining of functional genomic databases. Analysis of the Dependency Map, Connectivity Map, Cancer Cell Line Encyclopedia, and multiple protein-protein interaction databases yielded specific hypotheses about DUB function, a subset of which were confirmed in follow-on experiments. The data in this paper are browsable online in a newly developed DUB Portal and promise to improve understanding of DUBs as a family as well as the activities of incompletely characterized DUBs (e.g. USPL1 and USP32) and those already targeted with investigational cancer therapeutics (e.g. USP14, UCHL5, and USP7).
Gastroenterology
DETECT: Development of Technologies for Early HCC Detection
Tayob N
Hepatocellular carcinoma (HCC) is a leading cause of morbidity and mortality in patients with cirrhosis and the third most common cause of cancer-related deaths worldwide. Though considered to be a highly fatal cancer, with a 5-year survival rate of less than 15%, curative treatments (surgical resection, liver transplantation, ablation) are available for patients diagnosed at an early stage. U.S. professional society guidelines recommend HCC surveillance in patients with cirrhosis of any etiology with biannual ultrasound ± serum alpha-fetoprotein (AFP), which is associated with survival benefits and receipt of curative treatment. However, ultrasound ± AFP can be associated with physical harms, that is, the need for multiple contrast-enhanced cross-sectional imaging studies and biopsies driven by false-positive tests or indeterminate lesions. Moreover, several new challenges in HCC surveillance are emerging. Contemporary Western cirrhosis cohorts consist of a higher proportion of patients with hepatitis C virus (HCV) after sustained virologic response and nonalcoholic fatty liver disease (NAFLD) with a lower annual risk of HCC (1%–3%), compared with older cohorts with viremic HCV (3%–8%). However, given the high prevalence of NAFLD in the U.S., the population at risk is growing. Given cost and capacity concerns, screening all patients with NAFLD is not feasible. Similar challenges exist for patients with HCV-related cirrhosis who have been cured. In addition, ultrasound has several limitations, including operator dependence, limited visualization in selected patients (particularly in the setting of abdominal adiposity and hepatic steatosis), and low sensitivity for early HCC (?45%). Furthermore, given logistical barriers, imaging-based surveillance continues to be underutilized in clinical practice, with utilization rates of only 24%. Therefore, the current “one-size-fits-all” model of ultrasound-based surveillance should be challenged and the discovery of new approaches and biomarkers are warranted.
Gastroenterology
Arima K, Zhong R, Ugai T, Zhao M, Haruki K, Akimoto N, Lau MC, Okadome K, Mehta RS, Väyrynen JP, Kishikawa J, Twombly TS, Shi S, Fujiyoshi K, Kosumi K, Wang F, Wu K, Song M, Zhang X, Willett WC, Giovannucci EL, Meyerhardt JA, Garrett WS, Huttenhower C, Chan AT, Nowak JA, Giannakis M, Ogino S
BACKGROUND AND AIMS: Evidence supports a carcinogenic role of Escherichia coli carrying the polyketide synthase (pks) island that encodes enzymes for colibactin biosynthesis. We hypothesized that the association of western-style diet (rich in red and processed meat) with colorectal cancer incidence might be stronger for tumors containing higher amounts of pks+ E. coli.
METHODS: Western diet score was calculated using food frequency questionnaire data obtained every four years during follow-up of 134,775 participants in two U.S.-wide prospective cohort studies. Using quantitative polymerase chain reaction, we measured pks+ E. coli DNA in 1,175 tumors among 3,200 incident colorectal cancer cases that had occurred during the follow-up. We utilized the 3,200 cases and inverse probability weighting (to adjust for selection bias due to tissue availability), integrated in multivariable-adjusted duplication-method Cox proportional hazards regression analyses.
RESULTS: The association of the western diet score with colorectal cancer incidence was stronger for tumors containing higher levels of pks+ E. coli (Pheterogeneity = 0.014). Multivariable-adjusted hazard ratios (with 95% confidence interval) for the highest (vs. lowest) tertile of the western diet score were 3.45 (1.53-7.78) (Ptrend = 0.001) for pks+ E. coli-high tumors, 1.22 (0.57-2.63) for pks+ E. coli-low tumors, and 1.10 (0.85-1.42) for pks+ E. coli-negative tumors. The pks+ E. coli level was associated with lower disease stage but not with tumor location, microsatellite instability, or BRAF, KRAS, or PIK3CA mutations.
CONCLUSIONS: Western-style diet is associated with higher incidence of colorectal cancer containing abundant pks+ E. coli, supporting a potential link between diet, the intestinal microbiota, and colorectal carcinogenesis.
Journal of Clinical Oncology
Duma N
There I was, crying once again all the way from the hospital's parking lot to my apartment, into the shower, and while trying to fall asleep. This had become the norm during my internal medicine residency. For years, I tried hard every day to be someone else in order to fit in. It started with off-hand comments like “Look at her red shoes,” “You are so colorful,” and “You are so Latina.” These later escalated to being interrupted during presentations with comments about my accent, being told that my medical school training in my home country was inferior to my US colleagues, and being assigned all Spanish-speaking patients because “They are your people.” Some of those comments and interactions were unintentionally harmful but led to feelings of isolation, and over time, I began to feel like an outsider.
Journal of Clinical Oncology
Liu JF, Matulonis UA
PURPOSE: Platinum-based chemotherapy is the standard of care for platinum-sensitive ovarian cancer, but complications from repeated platinum therapy occur. We assessed the activity of two all-oral nonplatinum alternatives, olaparib or olaparib/cediranib, versus platinum-based chemotherapy.
PATIENTS AND METHODS: NRG-GY004 is an open-label, randomized, phase III trial conducted in the United States and Canada. Eligible patients had high-grade serous or endometrioid platinum-sensitive ovarian cancer. Patients were randomly assigned 1:1:1 to platinum-based chemotherapy, olaparib, or olaparib/cediranib. The primary end point was progression-free survival (PFS) in the intention-to-treat population. Secondary end points included activity within germline BRCA-mutated or wild-type subgroups and patient-reported outcomes (PROs).
RESULTS: Between February 04, 2016, and November 13, 2017, 565 eligible patients were randomly assigned. Median PFS was 10.3 (95% CI, 8.7 to 11.2), 8.2 (95% CI, 6.6 to 8.7), and 10.4 (95% CI, 8.5 to 12.5) months with chemotherapy, olaparib, and olaparib/cediranib, respectively. Olaparib/cediranib did not improve PFS versus chemotherapy (hazard ratio [HR] 0.86; 95% CI, 0.66 to 1.10; P = .077). In women with germline BRCA mutation, the PFS HR versus chemotherapy was 0.55 (95% CI, 0.32 to 0.94) for olaparib/cediranib and 0.63 (95% CI, 0.37 to 1.07) for olaparib. In women without a germline BRCA mutation, the PFS HR versus chemotherapy was 0.97 (95% CI, 0.73 to 1.30) for olaparib/cediranib and 1.41 (95% CI, 1.07 to 1.86) for olaparib. Hematologic adverse events occurred more commonly with chemotherapy; however, nonhematologic adverse events were higher with olaparib/cediranib. In 489 patients evaluable for PROs, patients receiving olaparib/cediranib scored on average 1.1 points worse on the NFOSI-DRS-P subscale (97.5% CI, -2.0 to -0.2, P = .0063) versus chemotherapy; no difference between olaparib and chemotherapy was observed.
CONCLUSION: Combination olaparib/cediranib did not improve PFS compared with chemotherapy and resulted in reduced PROs. Notably, in patients with a germline BRCA mutation, both olaparib and olaparib/cediranib had significant clinical activity.
Journal of Clinical Oncology
Sweeney CJ
We thank Marandino et al and agree that cognitive function is important and complex in men with metastatic, hormone-sensitive prostate cancer. Cognitive decline increases with age, as does the incidence of metastatic prostate cancer, and has been associated with a diagnosis of cancer, androgen deprivation therapy, early generation antiandrogens, novel androgen signaling inhibitors, and chemotherapy. ENZAMET provides unique information about self-ratings of cognitive function and other aspects of health-related quality of life (HRQoL) in men receiving these treatments for metastatic, hormone-sensitive prostate cancer.
JAMA Oncology
Aiming for the Cure in ERBB2-Positive Metastatic Breast Cancer-Should We Go "All In"?-Reply
Tarantino P, Parsons HA, Tolaney SM
In Reply We read with keen interest the comments from Drs Rala de Paula and Crocamo on our Review discussing strategies to improve long-term outcomes for ERBB2-positive metastatic breast cancer (MBC). We recognize that the definition of long-term response is not yet established. However, we find reasonable the 35-month cutoff proposed by the CLEOPATRA investigators, given that few progressions were observed in the trial after that point. Discontinuation for toxic effects was uncommon in both study arms (approximately 5%), and the treatments administered after discontinuation are described in the study publication. We concur that research is needed to optimize the duration of ERBB2 blockade in long-term responders, a question that we aim to address with the STOP HER2 trial, which will enroll patients with ERBB2-positive MBC who are progression free after 3 years or longer on first-line anti-ERBB2 therapy. Patients will stop anti-ERBB2 therapy with close follow-up and extensive biomarker assessment. A parallel, observational cohort will enroll patients who want to participate without stopping therapy.
JAMA Oncology
Ricciuti B, Wang X, Alessi JV, Mahadevan NR, Li YY, Polio A, Lindsay J, Umeton R, Sinha R, Recondo G, Lamberti G, Lawrence M, Vaz VR, Leonardi GC, Gupta H, Cherniack AD, Tolstorukov MY, Sharma B, Felt KD, Gainor JF, Ravi A, Getz G, Jänne PA, Van Allen EM, Nishino M, Sholl LM, Christiani DC, Lin X, Rodig SJ, Hellmann MD, Awad MM
IMPORTANCE: Although tumor mutation burden (TMB) has been explored as a potential biomarker of immunotherapy efficacy in solid tumors, there still is a lack of consensus about the optimal TMB threshold that best discriminates improved outcomes of immune checkpoint inhibitor therapy among patients with non-small cell lung cancer (NSCLC).
OBJECTIVES: To determine the association between increasing TMB levels and immunotherapy efficacy across clinically relevant programmed death ligand-1 (PD-L1) levels in patients with NSCLC.
DESIGN, SETTING, AND PARTICIPANTS: This multicenter cohort study included patients with advanced NSCLC treated with immunotherapy who received programmed cell death-1 (PD-1) or PD-L1 inhibition in the Dana-Farber Cancer Institute (DFCI), Memorial Sloan Kettering Cancer Center (MSKCC), and in the Stand Up To Cancer (SU2C)/Mark Foundation data sets. Clinicopathological and genomic data were collected from patients between September 2013 and September 2020. Data analysis was performed from November 2021 to February 2022.
EXPOSURES: Treatment with PD-1/PD-L1 inhibition without chemotherapy.
MAIN OUTCOMES AND MEASURES: Association of TMB levels with objective response rate (ORR), progression-free survival (PFS), and overall survival (OS).
RESULTS: In the entire cohort of 1552 patients with advanced NSCLC who received PD-1/PD-L1 blockade, the median (range) age was 66 (22-92) years, 830 (53.5%) were women, and 1347 (86.8%) had cancer with nonsquamous histologic profile. A regression tree modeling ORR as a function of TMB identified 2 TMB groupings in the discovery cohort (MSKCC), defined as low TMB (≤19.0 mutations per megabase) and high TMB (>19.0 mutations per megabase), which were associated with increasing improvements in ORR, PFS, and OS in the discovery cohort and in 2 independent cohorts (DFCI and SU2C/Mark Foundation). These TMB levels also were associated with significant improvements in outcomes of immunotherapy in each PD-L1 tumor proportion score subgroup of less than 1%, 1% to 49%, and 50% or higher. The ORR to PD-1/PD-L1 inhibition was as high as 57% in patients with high TMB and PD-L1 expression 50% or higher and as low as 8.7% in patients with low TMB and PD-L1 expression less than 1%. Multiplexed immunofluorescence and transcriptomic profiling revealed that high TMB levels were associated with increased CD8-positive, PD-L1-positive T-cell infiltration, increased PD-L1
expression on tumor and immune cells, and upregulation of innate and adaptive immune response signatures.
CONCLUSIONS AND RELEVANCE: These findings suggest that increasing TMB levels are associated with immune cell infiltration and an inflammatory T-cell-mediated response, resulting in increased sensitivity to PD-1/PD-L1 blockade in NSCLC across PD-L1 expression subgroups.
JAMA Oncology
Prognostic and Biologic Significance of ERBB2-Low Expression in Early-Stage Breast Cancer
Tarantino P, Jin Q, Tayob N, Jeselsohn RM, Schnitt SJ, Vincuilla J, Parker T, Tyekucheva S, Li T, Lin NU, Hughes ME, Weiss AC, King TA, Mittendorf EA, Tolaney SM
IMPORTANCE: It is unclear whether ERBB2-low breast cancer should be considered an individual biologic subtype distinct from ERBB2-0 breast cancer.
OBJECTIVE: To investigate whether low ERBB2 expression is associated with distinct clinicopathologic characteristics and prognosis among patients with hormone receptor (HR)-positive and triple-negative breast cancer (TNBC).
DESIGN, SETTING, AND PARTICIPANTS: This cohort study was conducted using data from a prospectively maintained institutional database on all consecutive patients with breast cancer undergoing surgery between January 2016 and March 2021 at Dana-Farber Brigham Cancer Center. The study included 5235 patients with stage I through III, ERBB2-negative invasive breast cancer. Tumors were classified as ERBB2-low if they had an ERBB2 immunohistochemical (IHC) score of 1+ or 2+ with negative in situ hybridization assay and ERBB2-0 if they had an ERBB2 IHC score of 0. Data were analyzed from September 2021 through January 2022.
EXPOSURES: Standard treatment according to institutional guidelines.
MAIN OUTCOMES AND MEASURES: Comparison of clinicopathologic characteristics and disease outcomes (pathologic complete response rate [pCR], disease-free survival, distant disease-free survival, and overall survival) between patients with ERBB2-low and ERBB2-0 breast cancer.
RESULTS: Among 5235 patients with ERBB2-negative invasive breast cancer (5191 [99.2%] women; median [range] age at primary surgery, 59.0 [21.0-95.0] years), 2917 patients (55.7%) and 2318 patients (44.3%) had ERBB2-low and ERBB2-0 tumors, respectively. Expression of HR was significantly more common among ERBB2-low compared with ERBB2-0 tumors (2643 patients [90.6%] vs 1895 patients [81.8%]; P < .001). The rate of ERBB2-low tumors increased progressively, from 296 of 739 estrogen receptor (ER)-negative tumors (40.1%) to 31 of 67 ER-low (ie, ER 1%-9%) tumors (46.3%), 37 of 67 ER-moderate (ie, ER, 10%-49%) tumors (55.2%), 2047 of 3542 ER-high (ie, ER, 50%-95%) tumors (57.8%), and 499 of 803 ER-very high (ie, ER > 95%) tumors (62.1%) (P < .001). Among 675 patients receiving neoadjuvant chemotherapy, those with ERBB2-0 tumors experienced higher pCR rates (95 patients [26.8%] vs 53 patients [16.6%]; P = .002). However, there were no statistically significant differences in pCR rate between ERBB2-low and ERBB2-0 tumors when separately analyzing HR-positive, ER-low, HR-positive without ER-low, or TNBC tumors. In exploratory survival analysis, no differences by ERBB2-low expression in disease-free survival, distant disease-free survival, or overall survival were observed among patients with HR-positive tumors or TNBC.
CONCLUSIONS AND RELEVANCE: The results of this cohort study did not support the interpretation of ERBB2-low breast cancer as a distinct biologic subtype. ERBB2-low expression was positively associated with level of ER expression, and ER-low tumors were enriched among ERBB2-0 tumors, suggesting that, given the worse prognosis of ER-low tumors, they may be associated with confounding of prognostic analyses of ERBB2-low expression.
JAMA Oncology
Starting a Career in Oncology: Fighting Cancer and Gender Disparities
Duma N
Identical degrees do not always lead to equal opportunity. I grew up as a child of 2 attorneys who graduated at the same time from the same law school, but only 1 faced gender bias throughout her career. In addition to encountering sexism and harassment while practicing law full-time, my mother was expected to care for me, my brother, and our home. Even with a supportive spouse, these obligations certainly influenced her career choices. My childhood’s household division-of-labor was not unique, and the field of medicine is not immune. A 2019 study reported that within just 6 years of completing medical training, women physicians are substantially more likely to report cutting back on their hours and cite family responsibilities as the major factor behind this career decision.1 This gap in work hours so early in a career may propagate further gender inequities, such as salary and future promotions.
Lancet Oncology
Choueiri TK
BACKGROUND: In the primary analysis of CheckMate 9ER, nivolumab plus cabozantinib showed superior progression-free survival, overall survival, and objective response over sunitinib in patients with previously untreated advanced renal cell carcinoma (median follow-up of 18¬?1 months). Here, we report extended follow-up of overall survival and updated efficacy and safety.
METHODS: This open-label, randomised, phase 3 trial was done in 125 hospitals and cancer centres across 18 countries. We included patients aged 18 years or older with previously untreated advanced or metastatic clear-cell renal cell carcinoma, a Karnofsky performance status of 70% or higher, measurable disease according to Response Evaluation Criteria in Solid Tumors version 1.1 assessed by the investigator, any International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic risk category, and available tumour tissue for PD-L1 testing. Patients were randomly assigned (1:1) to nivolumab (240 mg) intravenously every 2 weeks plus cabozantinib (40 mg) orally once daily or sunitinib (50 mg orally) once daily (4 weeks per 6-week cycle). Randomisation, stratified by IMDC risk status, tumour PD-L1 expression, and geographical region, was done by permuted block within each stratum using a block size of four, via an interactive response system. The primary endpoint was progression-free survival by blinded independent central review. Overall survival was a secondary endpoint (reported here as the preplanned final analysis according to the protocol). Efficacy was assessed in all randomly assigned patients; safety was assessed in all patients who received at least one dose of any study drug. This ongoing study, closed to recruitment, is registered with ClinicalTrials.gov, NCT03141177.
FINDINGS: Between Sept 11, 2017, and May 14, 2019, 323 patients were randomly assigned to the nivolumab plus cabozantinib group and 328 to the sunitinib group. With an extended follow-up (data cutoff of June 24, 2021; median 32¬?9 months [IQR 30¬?4-35¬?9]), median overall survival was 37¬?7 months (95% CI 35¬?5-not estimable) in the nivolumab plus cabozantinib group and 34¬?3 months (29¬?0-not estimable) in the sunitinib group (hazard ratio [HR] 0¬?70 [95% CI 0¬?55-0¬?90], p=0¬?0043) and updated median progression-free survival was 16¬?6 months (12¬?8-19¬?8) versus 8¬?3 months (7¬?0-9¬?7; HR 0¬?56 [95% CI 0¬?46-0¬?68], p<0¬?0001). Grade 3-4 treatment-related adverse events occurred in 208 (65%) of 320 patients with nivolumab plus cabozantinib versus 172 (54%) of 320 with sunitinib. The most common grade 3-4 treatment-related adverse events were hypertension (40 [13%] of 320 patients in the nivolumab plus cabozantinib group vs 39 [12%] of 320 in the sunitinib group), palmar-plantar erythrodysaesthesia (25 [8%] vs 26 [8%]), and diarrhoea (22 [7%] vs 15 [5%]). Grade 3-4 treatment-related serious adverse events occurred in 70 (22%) of 320 patients in the nivolumab plus cabozantinib group and 31 (10%) of 320 in the cabozantinib group. One additional treatment-related death occurred with sunitinib (sudden death).
INTERPRETATION: With extended follow-up and preplanned final overall survival analysis per protocol, nivolumab plus cabozantinib demonstrated improved efficacy versus sunitinib, further supporting the combination in the first-line treatment of advanced renal cell carcinoma.
FUNDING: Bristol Myers Squibb and Ono Pharmaceutical.
Nature Communications
Allosteric Inhibition of PPM1D Serine/Threonine Phosphatase Via an Altered Conformational State
Miller PG, Sathappa M, Moroco JA, Jiang W, Qian Y, Iqbal S, Guo Q, Giacomelli AO, Shaw S, Vernier C, Bajrami B, Yang X, Raffier C, Sperling AS, Gibson CJ, Kahn J, Jin C, Ranaghan M, Caliman A, Brousseau M, Fischer ES, Lintner R, Piccioni F, Campbell AJ, Root DE, Garvie CW, Ebert BL
PPM1D encodes a serine/threonine phosphatase that regulates numerous pathways including the DNA damage response and p53. Activating mutations and amplification of PPM1D are found across numerous cancer types. GSK2830371 is a potent and selective allosteric inhibitor of PPM1D, but its mechanism of binding and inhibition of catalytic activity are unknown. Here we use computational, biochemical and functional genetic studies to elucidate the molecular basis of GSK2830371 activity. These data confirm that GSK2830371 binds an allosteric site of PPM1D with high affinity. By further incorporating data from hydrogen deuterium exchange mass spectrometry and sedimentation velocity analytical ultracentrifugation, we demonstrate that PPM1D exists in an equilibrium between two conformations that are defined by the movement of the flap domain, which is required for substrate recognition. A hinge region was identified that is critical for switching between the two conformations and was directly implicated in the high-affinity binding of GSK2830371 to PPM1D. We propose that the two conformations represent active and inactive forms of the protein reflected by the position of the flap, and that binding of GSK2830371 shifts the equilibrium to the inactive form. Finally, we found that C-terminal truncating mutations proximal to residue 400 result in destabilization of the protein via loss of a stabilizing N- and C-terminal interaction, consistent with the observation from human genetic data that nearly all PPM1D mutations in cancer are truncating and occur distal to residue 400. Taken together, our findings elucidate the mechanism by which binding of a small molecule to an allosteric site of PPM1D inhibits its activity and provides insights into the biology of PPM1D.
Nature Communications
Structural Basis for Defective Membrane Targeting of Mutant Enzyme in Human VLCAD Deficiency
Prew MS, Camara CM, Bloch NB, Levy HR, Seo HS, Dhe-Paganon S, Bird GH, Herce HD, Gygi MA, Escudero S, Walensky LD
Very long-chain acyl-CoA dehydrogenase (VLCAD) is an inner mitochondrial membrane enzyme that catalyzes the first and rate-limiting step of long-chain fatty acid oxidation. Point mutations in human VLCAD can produce an inborn error of metabolism called VLCAD deficiency that can lead to severe pathophysiologic consequences, including cardiomyopathy, hypoglycemia, and rhabdomyolysis. Discrete mutations in a structurally-uncharacterized C-terminal domain region of VLCAD cause enzymatic deficiency by an incompletely defined mechanism. Here, we conducted a structure-function study, incorporating X-ray crystallography, hydrogen-deuterium exchange mass spectrometry, computational modeling, and biochemical analyses, to characterize a specific membrane interaction defect of full-length, human VLCAD bearing the clinically-observed mutations, A450P or L462P. By disrupting a predicted α-helical hairpin, these mutations either partially or completely impair direct interaction with the membrane itself. Thus, our data support a structural basis for VLCAD deficiency in patients with discrete mutations in an ?-helical membrane-binding motif, resulting in pathologic enzyme mislocalization.
Nature Medicine
Molecular Profiling Identifies Targeted Therapy Opportunities in Pediatric Solid Cancer
Church AJ, Corson LB, Kao PC, Imamovic-Tuco A, Reidy D, Doan D, Harris H, Manning D, Al-Ibraheemi A, Li Y, Gupta H, Cherniack AD, Lo YC, Strand GR, Lee LA, Pinches RS, Lazo De La Vega L, Harden MV, Lennon NJ, Comeau H, Harris MH, Forrest SJ, Clinton CM, Crompton BD, Kamihara J, MacConaill LE, Lindeman NI, Van Allen E, DuBois SG, London WB, Janeway KA
To evaluate the clinical impact of molecular tumor profiling (MTP) with targeted sequencing panel tests, pediatric patients with extracranial solid tumors were enrolled in a prospective observational cohort study at 12 institutions. In the 345-patient analytical population, median age at diagnosis was 12 years (range 0-27.5); 298 patients (86%) had 1 or more alterations with potential for impact on care. Genomic alterations with diagnostic, prognostic or therapeutic significance were present in 61, 16 and 65% of patients, respectively. After return of the results, impact on care included 17 patients with a clarified diagnostic classification and 240 patients with an MTP result that could be used to select molecularly targeted therapy matched to identified alterations (MTT). Of the 29 patients who received MTT, 24% had an objective response or experienced durable clinical benefit; all but 1 of these patients received targeted therapy matched to a gene fusion. Of the diagnostic variants identified in 209 patients, 77% were gene fusions. MTP with targeted panel tests that includes fusion detection has a substantial clinical impact for young patients with solid tumors.
Proceedings of the National Academy of Sciences of the U.S.A.
Dong H(1), Vergara J, Liang Y, Ali A, Tarannum M, Baginska J, Abdulhamid Y, Dinh K, Soiffer RJ, Ritz J, Glimcher LH, Romee R
Acute myeloid leukemia (AML) remains a therapeutic challenge, and a paucity of tumor-specific targets has significantly hampered the development of effective immune-based therapies. Recent paradigm-changing studies have shown that natural killer (NK) cells exhibit innate memory upon brief activation with IL-12 and IL-18, leading to cytokine-induced memory-like (CIML) NK cell differentiation. CIML NK cells have enhanced antitumor activity and have shown promising results in early phase clinical trials in patients with relapsed/refractory AML. Here, we show that arming CIML NK cells with a neoepitope-specific chimeric antigen receptor (CAR) significantly enhances their antitumor responses to nucleophosphmin-1 (NPM1)-mutated AML while avoiding off-target toxicity. CIML NK cells differentiated from peripheral blood NK cells were efficiently transduced to express a TCR-like CAR that specifically recognizes a neoepitope derived from the cytosolic oncogenic NPM1-mutated protein presented by HLA-A2. These CAR CIML NK cells displayed enhanced activity against NPM1-mutated AML cell lines and patient-derived leukemic blast cells. CAR CIML NK cells persisted in vivo and significantly improved AML outcomes in xenograft models. Single-cell RNA sequencing and mass cytometry analyses identified up-regulation of cell proliferation, protein folding, immune responses, and major metabolic pathways in CAR-transduced CIML NK cells, resulting in tumor-specific, CAR-dependent activation and function in response to AML target cells. Thus, efficient arming of CIML NK cells with an NPM1-mutation-specific TCR-like CAR substantially improves their innate antitumor responses against an otherwise intracellular mutant protein. These preclinical findings justify evaluating this approach in clinical trials in HLA-A2+ AML patients with NPM1c mutations.
American Journal of Hematology
Castillo JJ
Analytical Chemistry
Zhu H, Chan WC, Ficarro SB, Tavares I, Bratt AS, Buhrlage SJ, Marto JA
Annals of Surgical Oncology
Kantor O, Weiss A, Burstein HJ, Mittendorf EA, King TA
Biostatistics
A Probabilistic Gene Expression Barcode for Annotation of Cell Types from Single-Cell RNA-Seq Data
Grabski IN, Irizarry RA
Blood Cancer Discovery
Transcriptional Plasticity Drives Leukemia Immune Escape
Eagle K, Harada T, Kalfon J, Perez MW, Heshmati Y, Ewers J, Dempster JM, Kugener G, Stegmaier K, Orkin SH, Pimkin M
British Journal of Haematology
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Breast Cancer Research and Treatment
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Breast Cancer Research and Treatment
Sella T, Ren S, Freret TS, Economy KE, Chen WY, Parsons HA, Lin NU, Moy B, Tung NM, Partridge AH, Tayob N, Mayer EL
Breast Cancer Research and Treatment
Sella T, Kantor O, Weiss A, Partridge AH, Metzger O, King TA
Cancer Immunology Research
Song L, Ouyang Z, Cohen D, Cao Y, Altreuter J, Bai G, Hu X, Livak KJ, Li H, Tang M, Liu XS
Cancer Immunology Research
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Cancer Nursing
Stability of Symptom Clusters in Patients with Gynecologic Cancer Receiving Chemotherapy
Pozzar RA, Hammer MJ
Cancer Research
Berchuck JE, Adib E, Abou Alaiwi S, Bell C, McClure HM, El Zarif T, Davidsohn MP, Lakshminarayanan G, Kelleher KM, Seo JH, Pomerantz MM, Freedman ML
ChemMedChem
Light-Controllable Binary Switch Activation of CAR T Cells
Kobayashi A, Nobili A, Neier SC, Sadiki A, Distel R, Novina CD
Clinical Cancer Research
Linking Genotype to Phenotype: Bench to Bedside
George S, Bertagnolli MM
Clinical Lymphoma, Myeloma and Leukemia
Luskin MR
Critical Reviews in Oncology/Hematology
Riaz IB, Xu W
EClinicalMedicine
Breast Cancer Awareness Among Afghan Refugee Women in Turkey
Faggen M, Warren L, Wong J, Punglia R, Bellon J, Sayan M
European Journal of Cancer
Albiges L, Choueiri T, Signoretti S
Genes and Development
Cell and Chromatin Transitions in Intestinal Stem Cell Regeneration
Singh PNP, Madha S, Shivdasani RA
Hematology/Oncology Clinics of North America
Gene Therapy for Pediatric Neurologic Disease
Jimenez-Kurlander L, Duncan CN
Journal of the American Society of Nephrology
Gelfand SL
Journal of Clinical Investigation
Sellar RS, Sperling AS, Slabicki M, Gasser JA, McConkey ME, Donovan KA, Mageed N, Adams DN, Zou C, Miller PG, Dutta RK, Lin AE, Sandoval BE, Quevedo Barrios VA, Shkolnik V, Koeppel J, Fink EC, Bergstrom EJ, Burt R, Udeshi ND, Carr SA, Fischer ES, Ebert BL
Journal of Clinical Investigation
Reversal of Viral and Epigenetic HLA Class I Repression in Merkel Cell Carcinoma
Lee PC, Klaeger S, Le PM, Cheng J, Ananthapadmanabhan V, Frost TC, Stevens JD, Wong AY, Iorgulescu JB, Tarren AY, Chea VA, Carulli IP, Gartin AK, Sarkizova S, Wright KT, Li LW, Nomburg J, Li S, Huang T, Liu X, Pomerance L, Doherty LM, Apffel AM, Wallace LJ, Rachimi S, Felt KD, Wolff JO, Witten E, Zhang W, Neuberg D, Lane WJ, Thakuria M, Rodig SJ, Clauser KR, Doench JG, Buhrlage SJ, Carr SA, DeCaprio JA, Wu CJ, Keskin DB
Journal of Pain and Symptom Management
Identification of Distinct Symptom Profiles in Cancer Patients Using a Pre-Specified Symptom Cluster
Hammer MJ
Journal of Palliative Medicine
Osman H
MethodsX
Koeller DR, Manning DK, Schwartz A, Chittenden A, Hayes CP, Abraamyan F, Rana HQ, Lindeman NI, Garber JE, Ghazani AA
Nature Reviews Cancer
Structural Variations in Cancer and the 3D Genome
Dubois F, Beroukhim R
Nature Reviews Neurology
Berger T, Wen PY
Neuro-Oncology
Aizer AA, Lamba N, Brastianos PK, Camidge DR, Huang RY, Lee EQ, Lin NU, Parsons M, Reardon DA, Wen PY
NPJ Precision Oncology
Dillon KM, Bekele RT, Hanlon T, Rafiei S, Szallasi Z, Choudhury AD, Mouw KW
Pediatric Blood and Cancer
Pollock NI, Flamand Y, Zhu J, Millington K, Stevenson K, Silverman LB, Vrooman LM, Cohen LE
Pediatric Blood and Cancer
Kempf AM, Guss CE, Millington K, Pilcher S, Boyle PJ, Charlton BM, Haas-Kogan DA, Liu KX
Pediatric Blood and Cancer
Gotti G, Stevenson K, Kay-Green S, Blonquist TM, Mantagos JS, Silverman LB, Place AE
STAR Protocols
Abrecht C, Hallisey M, Dennis J, Nazzaro M, Brainard M, Hathaway E, Schork AN, Hodi FS, Severgnini M, Baginska J
Trials
Hassett MJ, Uno H, Cronin C