Blood
Decoding Cost-Effectiveness of PNH Therapies
Kelkar AH, Abel GA
In this issue of Blood, Ito et al present a compelling cost-effectiveness analysis of iptacopan for patients with paroxysmal nocturnal hemoglobinuria (PNH) who have suboptimal responses to the high-priced IV C5 inhibitors eculizumab and ravulizumab. Although C5 inhibitors were groundbreaking in their ability to target the terminal complement cascade and reduce intravascular hemolysis, they often left patients with persistent extravascular hemolysis and the burden of frequent infusions and transfusions. The advent of newer PNH therapies targeting earlier steps in the complement cascade, such as the subcutaneous C3 inhibitor pegcetacoplan and the oral factor B inhibitor iptacopan, has ushered in a new era of treatment possibilities, offering the potential for improved control of both intravascular and extravascular hemolysis. The study1 demonstrates that iptacopan not only improves outcomes for these patients but also yields long-term cost savings. This is a rare finding in independent cost-effectiveness analyses and challenges prior assessments questioning the economic value of iptacopan.
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Blood
The Current Landscape of Frontline Large B-Cell Lymphoma Trials
Qualls D, Armand P
At least 25% to 35% of patients with large B-cell lymphoma (LBCL) are not cured with frontline treatment, with generally poor subsequent outcomes. This motivates ongoing and intense interest in improving the frontline treatment of this disease. R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) has remained the standard of care for 20 years despite dozens of trials aiming to improve upon this regimen, and only recently has a novel regimen (pola-R-CHP [polatuzumab vedotin, rituximab, cyclophosphamide, doxorubicin, and prednisone]) challenged its supremacy. Fortunately, at least 15 promising randomized trials evaluating new treatments in frontline LBCL treatment are underway. They differ not only in the therapy evaluated in the experimental arm, but in the choice of control arm, primary end point, and patient selection strategy, with some targeting specific biologic subtypes, some focusing on specific high-risk patient populations, and others enrolling older or frail patients. Novel response-adapted strategies leveraging circulating tumor DNA are also underway. Although this variety of approaches provides a welcome increase in the overall likelihood of success, it will also present challenges if several of these trials are successful and we must choose among multiple potential treatment options that were not all tested in the same fashion. In this review, we summarize the main ongoing frontline randomized trials and discuss some of the questions that we will face in interpreting and applying their results in clinical practice in the next few years.
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Cancer Cell
Cytokines in Cancer
Kureshi CT, Dougan SK
Cytokines are proteins used by immune cells to communicate with each other and with cells in their environment. The pleiotropic effects of cytokine networks are determined by which cells express cytokines and which cells express cytokine receptors, with downstream outcomes that can differ based on cell type and environmental cues. Certain cytokines, such as interferon (IFN)-?, have been clearly linked to anti-tumor immunity, while others, such as the innate inflammatory cytokines, promote oncogenesis. Here we provide an overview of the functional roles of cytokines in the tumor microenvironment. Although we have a sophisticated understanding of cytokine networks, therapeutically targeting cytokine pathways in cancer has been challenging. We discuss current progress in cytokine blockade, cytokine-based therapies, and engineered cytokine therapeutics as emerging cancer treatments of interest.
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Cell Stem Cell
Regulated GATA1 Expression as a Universal Gene Therapy for Diamond-Blackfan Anemia
Voit RA, Liao X, Caulier A, Antoszewski M, Cohen B, Armant M, Lu HY, Fleming TJ, Kamal E, Wahlster L, Huang MM, Clarke W, Perez-Atayde A, Pellin D, Shimamura A, Williams DA, Sankaran VG
Gene therapy using hematopoietic stem and progenitor cells is altering the therapeutic landscape for patients with hematologic, immunologic, and metabolic disorders but has not yet been successfully developed for individuals with the bone marrow failure syndrome Diamond-Blackfan anemia (DBA). More than 30 mutations cause DBA through impaired ribosome function and lead to inefficient translation of the erythroid master regulator GATA1, providing a potential avenue for therapeutic intervention applicable to all patients with DBA, irrespective of the underlying genotype. Here, we report the development of a clinical-grade lentiviral gene therapy that achieves erythroid lineage-restricted expression of GATA1. We show that this vector is capable of augmenting erythropoiesis in DBA models and diverse patient samples without impacting hematopoietic stem cell function or demonstrating any signs of premalignant clonal expansion. These preclinical safety and efficacy data provide strong support for the first-in-human universal gene therapy trial for DBA through regulated GATA1 expression.
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Journal of Clinical Oncology
Adjuvant Dose-Dense Chemotherapy in Hormone Receptor-Positive Breast Cancer
Metzger Filho O, Ligibel J, Partridge A, Winer EP
PURPOSE: In light of evolving evidence that some patients with node-positive estrogen receptor-positive (ER+) disease may receive less benefit from chemotherapy, this study reports 12-year outcomes of the C9741 trial overall, and by the sensitivity to endocrine therapy (SET2,3) test index, a biomarker measuring endocrine transcriptional activity, to identify patients most likely to benefit from dose-dense chemotherapy.
METHODS: In all, 1,973 patients were randomly assigned to dose-dense versus conventional chemotherapy. Hazard ratios (HRs) for prognosis and for predictive interaction with chemotherapy schedule were estimated from Cox models of long-term disease-free survival (DFS) and overall survival (OS). SET2,3 was tested on the 682 banked RNA samples from ER+ cancers.
RESULTS: Dose-dense chemotherapy improved DFS in the overall study population by 23% (HR, 0.77 [95% CI, 0.66 to 0.90]) and OS by 20% (HR, 0.80 [95% CI, 0.67 to 0.95]); the benefits of dose-dense therapy were seen for ER+ and ER-negative subsets, without significant interaction between treatment arm and ER status. Low SET2,3 status was highly prognostic, but also predicted improved outcomes from dose-dense chemotherapy (interaction P = .0998 for DFS; 0.027 for OS), independent of menopausal status. Specifically, low endocrine transcriptional activity predicted benefit from dose-dense chemotherapy, whereas tumor burden and proliferation-driven signatures for molecular subtype classification did not.
CONCLUSION: At 12-year follow-up, C9741 confirmed the sustained long-term benefit of adjuvant dose-dense chemotherapy for node-positive breast cancer. SET2,3 identified patients with ER+ breast cancer who benefited from dose-dense chemotherapy, and specifically, this benefit was predicted by low endocrine activity in the cancer, rather than tumor burden, molecular subtype, or menopausal status.
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Journal of Clinical Oncology
Datopotamab Deruxtecan in Advanced or Metastatic Non-Small Cell Lung Cancer with Actionable Genomic Alterations: Results from the Phase II TROPION-Lung05 Study
Sands J, Ahn MJ, Lisberg A, Cho BC, Blumenschein G Jr, Shum E, Pons Tostivint E, Goto Y, Heist R, Baas P, Planchard D, Pérol M, Felip E, Su WC, Paz-Ares L
PURPOSE: Datopotamab deruxtecan (Dato-DXd) is a trophoblast cell-surface antigen-2-directed antibody-drug conjugate with a highly potent topoisomerase I inhibitor payload. The TROPION-Lung05 phase II trial (ClinicalTrials.gov identifier: NCT04484142) evaluated the safety and clinical activity of Dato-DXd in patients with advanced/metastatic non-small cell lung cancer (NSCLC) with actionable genomic alterations progressing on or after targeted therapy and platinum-based chemotherapy.
PATIENTS AND METHODS: Patients received Dato-DXd 6 mg/kg once every 3 weeks. The primary end point was objective response rate (ORR) by blinded independent central review. Secondary end points included duration of response (DOR), safety, tolerability, and survival.
RESULTS: Among 137 patients who received at least 1 dose of Dato-DXd, 71.5% received at least three lines of prior therapies for advanced/metastatic disease. Overall, 56.9% had EGFR mutations and 24.8% had ALK rearrangements. Median treatment duration was 4.4 months (range, 0.7-20.6). The confirmed ORR was 35.8% (95% CI, 27.8 to 44.4) overall, and 43.6% (95% CI, 32.4 to 55.3) and 23.5% (95% CI, 10.7 to 41.2) in those with EGFR mutations and ALK rearrangements, respectively. The median DOR was 7.0 months (95% CI, 4.2 to 9.8), and the overall disease control rate was 78.8% (95% CI, 71.0 to 85.3). Grade ?3 treatment-related adverse events (TRAEs) occurred in 28.5% of patients. The most common TRAE was stomatitis (preferred term; any grade: 56.2%; grade ?3: 9.5%). Five (3.6%) patients experienced adjudicated treatment-related interstitial lung disease/pneumonitis, with 1 (0.7%) grade 5 event.
CONCLUSION: Encouraging and durable antitumor activity was observed with Dato-DXd in this heavily pretreated advanced/metastatic NSCLC population with actionable genomic alterations. The rate of treatment-related grade ?3 toxicities was comparable with previous observations, and no new safety signals were observed.
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Journal of Clinical Oncology
Neoadjuvant Nivolumab Plus Ipilimumab Versus Chemotherapy in Resectable Lung Cancer
Awad MM, Swanson SJ
PURPOSE: Neoadjuvant immune checkpoint blockade with nivolumab plus ipilimumab improves overall survival (OS) in non-small cell lung cancer (NSCLC); however, randomized data for resectable lung cancer are limited. We report results from the exploratory concurrently randomized nivolumab plus ipilimumab and chemotherapy arms of the international phase III CheckMate 816 trial.
METHODS: Adults with stage IB-IIIA (American Joint Committee on Cancer seventh edition) resectable NSCLC received three cycles of nivolumab once every 2 weeks plus one cycle of ipilimumab or three cycles of chemotherapy (on day 1 or days 1 and 8 of each 3-week cycle) followed by surgery. Analyses included event-free survival (EFS), OS, pathologic response, surgical outcomes, biomarker analyses, and safety.
RESULTS: A total of 221 patients were concurrently randomly assigned to nivolumab plus ipilimumab (n = 113) or chemotherapy (n = 108). At a median follow-up of 49.2 months, the median EFS was 54.8 months (95% CI, 24.4 to not reached [NR]) with nivolumab plus ipilimumab versus 20.9 months (95% CI, 14.2 to NR) with chemotherapy (HR, 0.77 [95% CI, 0.51 to 1.15]); 3-year EFS rates were 56% versus 44%. Higher rates of EFS events were initially seen, with later benefit favoring nivolumab plus ipilimumab; 3-year OS rates were 73% versus 61% (HR, 0.73 [95% CI, 0.47 to 1.14]); pathologic complete response rates were 20.4% versus 4.6%, respectively. In the respective arms, 83 (74%) and 82 patients (76%) underwent definitive surgery. Grade 3-4 treatment-related adverse events occurred in 14% and 36% of patients, respectively.
CONCLUSION: Neoadjuvant nivolumab plus ipilimumab showed potential long-term clinical benefit versus chemotherapy, despite early crossing of EFS curves in the preoperative phase and a lower rate of high-grade toxicity.
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Journal of Clinical Oncology
Revumenib Revises the Treatment Landscape for KMT2A-r Leukemia
Heikamp EB, Armstrong SA
Menin inhibitors are a novel class of small molecules that are being developed for leukemias harboring chromosomal rearrangements involving the lysine methyltransferase 2A gene (KMT2A-r), since Menin is a molecular dependency in this genetic subtype of leukemia. Issa et al report remarkable results from a phase I/II clinical trial of the Menin inhibitor revumenib (Syndax Pharmaceuticals) in a group of patients with heavily pretreated, relapsed/refractory (R/R) KMT2A-r leukemia. On the basis of the detailed understanding of the mechanisms of action of Menin inhibitors, the potential clinical indications are expanding and include patients with a common form of adult acute myeloid leukemia (AML) driven by mutations in the nucleophosmin (NPM1) gene, in addition to a growing list of leukemias driven by dysregulation of HOX/MEIS gene expression.
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Journal of Clinical Oncology
Targeting CD30 in Diffuse Large B-Cell Lymphoma: Where Does It Fit In?
Crombie JL, LaCasce AS
Over the past 5 years, the treatment landscape of relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) has evolved dramatically with the introduction of anti-CD19 chimeric antigen receptor (CAR) T-cell therapy and other novel agents. CAR T-cell therapy has become the preferred treatment choice for eligible patients in the second-line setting on the basis of the results of the ZUMA-7 and TRANSFORM trials, one of which included an overall survival (OS) benefit. Despite the promise of CAR T-cell therapy, patient eligibility, access to care, and treatment logistics continue to be barriers for many patients. In addition, a large subset of patients will ultimately relapse.
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Journal of the National Cancer Institute
Plant-Based Diet and Survival Among Patients with Metastatic Colorectal Cancer
Ma C, Ng K, Meyerhardt JA
BACKGROUND: A plant-based diet is associated with better survival among patients with nonmetastatic colorectal cancer (CRC), but its association in metastatic CRC is unknown.
METHODS: Using a National Cancer Institute-sponsored trial (CALGB/SWOG 80405), we included 1284 patients who completed validated food frequency questionnaires at the initiation of metastatic CRC treatment. We calculated 3 indices: overall plant-based diet index (PDI), which emphasized consumption of all plant foods while reducing animal food intake; healthful plant-based diet index (hPDI), which emphasized consumption of healthful plant foods such as whole grains, fruits, and vegetables; and unhealthful plant-based diet index (uPDI), which emphasized consumption of less healthful plant foods such as fruit juices, refined grains, and sugar-sweetened beverages. We estimated the associations of 3 indices (quintiles) with overall survival (OS) and progression-free survival (PFS) using multivariable Cox proportional hazards regression.
RESULTS: We observed 1100 deaths and 1204 progression events (median follow-up = 6.1?years). Compared with the lowest quintile, patients in the highest quintile of PDI had significantly better survival (hazard ratio [HR] for OS = 0.76 [0.62-0.94], Ptrend?=?.004; PFS = 0.81 [0.66-0.99], Ptrend?=?.09). Similar findings were observed for hPDI (HR for OS = 0.81 [0.65-1.01], Ptrend?=?.053; PFS = 0.80 [0.65-0.98], Ptrend?=?.04), whereas uPDI was not associated with worse survival (HR for OS = 1.16 [0.94-1.43], Ptrend?=?.21; PFS = 1.12 [0.92-1.36], Ptrend?=?.42).
CONCLUSIONS: Our study suggests that a plant-based diet, especially when rich in healthful plant foods, is associated with better survival among patients with metastatic CRC. The cause of survival benefits warrants further investigation.
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JAMA
Allogeneic Stem Cell Donation
Amonoo HL
Hematopoietic stem cell transplant (HSCT) is a potentially life-saving therapy for hematologic and bone marrow cancers (eg, leukemia, lymphoma, multiple myeloma, and myelodysplastic syndromes) and nonmalignant conditions (eg, sickle cell disease, aplastic anemia) in adults and children. Autologous stem cell transplant (auto-HSCT) involves the transplant of a patient’s own stem cells, while allogeneic stem cell transplant (allo-HSCT) involves the transplant of a related or unrelated donor’s stem cells (eTable in the Supplement). The Center for International Blood and Marrow Transplant Research reported that approximately 20?000 HSCTs were performed in the US in 2023, of which 11?139 were auto-HSCT and 8218 were allo-HSCT.
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JAMA
Expanding Palliative Care Access-Bridging Gaps in Diverse Clinical Settings
Amonoo HL
Palliative care has become standard in many inpatient settings, with about three-quarters of US hospitals currently offering such services. Although early integration of palliative care can yield substantial benefits for patients and their caregivers (eg, enhanced quality of life, psychological well-being, improved coping), the optimal timing and best clinical settings for initiating palliative care are not yet established.
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JAMA Oncology
Shared Local Oncology Care After Allogeneic Hematopoietic Cell Transplantation: A Randomized Clinical Trial
Abel GA, Kim HT, Bailey AS, Walsh JH, Walsh TP, Ivanov A, Faggen MA, Joyce AC, Close SD, Emmert A, Koreth J, Antin JH, Cutler CS, Ho VT, Soiffer RJ
IMPORTANCE: Although sharing care with local oncologists after allogeneic hematopoietic cell transplantation (HCT) has been proposed for patients living far from HCT centers, it is not known whether a shared strategy is safe or improves patient quality of life (QOL).
OBJECTIVE: To determine the efficacy and safety of sharing follow-up care after HCT between the HCT specialty center and local oncologists.
DESIGN, SETTING, AND PARTICIPANTS: This was a multicenter collaborative randomized clinical trial of patients undergoing HCT at Dana-Farber Cancer Institute (DFCI)-a high volume HCT center in Boston (Massachusetts)-and 8 local oncology practices. Eligible patients were enrolled from December 2017 to December 2021 and were randomized 1:1 to shared vs usual care after neutrophil engraftment, stratified by local sites in Massachusetts, Rhode Island, New Hampshire, New York, and Maine. Data analyses were performed in January 2024.
INTERVENTION: Shared care involved alternating post-HCT visits at DFCI and local oncology practices through day 100; for usual care, all post-HCT visits occurred only at DFCI.
MAIN OUTCOMES AND MEASURES: Coprimary outcomes were nonrelapse mortality (NRM) at day 100, and QOL measured by the FACT-BMT (Functional Assessment of Cancer Therapy-Bone Marrow Transplantation) instrument and the QLQ-C30 (European Organization for Research and Treatment of Cancer's Quality of Life Questionnaire) at day 180. Prespecified secondary outcomes included day 100 QOL and 1-year overall survival.
RESULTS: A total of 302 participants (median [range] age, 63 [20-79] years; 117 [38.7%] females; 185 [61.3%] males) were included in the analysis; 152 were randomized to shared care and 150 to usual care. Day 100 NRM was noninferior for shared vs usual care (2.6% [95% CI, 0.7% to 6.6%] vs 2.7% [95% CI, 0.7% to 6.7%]; P = .98). There were no differences at day 180 for the FACT-BMT total score (mean difference, 3.8; 95% CI, -2.1 to 9.6; P = .20) or QLQ-C30 global score (1.9; 95% CI, -4.9 to 8.8; P = .58). At day 100, the FACT-BMT total score was better for shared care (mean difference, 6.6; 95% CI, 1.0 to 12.1; P = .02) as was the QLQ-C30 global score (8.8; 95% CI, 1.8 to 15.7; P = .02).
CONCLUSIONS AND RELEVANCE: This randomized clinical trial found that shared care resulted in noninferior NRM at day 100 but similar QOL at day 180, with improved QOL at day 100. These data suggest that shared care is safe, improves QOL early on, and has the potential to become a routine model for post-HCT care.
TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03244826.
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Lancet
iPSC-Derived CD19 CAR NK Cells for Relapsed or Refractory Lymphoma
Shapiro RM, Romee R
Chimeric antigen receptor (CAR) T-cell therapy has revolutionised immunotherapy; however, prolonged manufacturing times, high cost, and limited accessibility remain a challenge. Allogeneic products offer a readily available off-the-shelf therapeutic modality with healthy donor cells that can be dosed multiple times. However, allogeneic therapies have their own limitations, including donor-specific variability in composition and efficacy, limited persistence due to allogeneic rejection, and the risk of graft-versus-host disease (GVHD). Induced pluripotent stem-cell (iPSC)-derived natural killer (NK) cells overcome substantial donor-specific variability as they are produced from a genetically well characterised clonal master cell bank that is amenable to engineered transgenic manipulation with defined copy number and integration sites.
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Lancet Oncology
Belzutifan Plus Cabozantinib as First-Line Treatment for Patients with Advanced Clear-Cell Renal Cell Carcinoma (LITESPARK-003): An Open-Label, Single-Arm, Phase 2 Study
Choueiri TK, McDermott DF, Arrowsmith E, Michaelson MD
BACKGROUND: Belzutifan, a first-in-class HIF-2? inhibitor, has shown antitumour activity as monotherapy and in combination with cabozantinib in patients with previously treated advanced kidney cancer. The phase 2 LITESPARK-003 study was designed to determine the antitumour activity and safety of belzutifan in combination with cabozantinib in patients with advanced clear-cell renal cell carcinoma that was previously untreated (cohort 1) or previously treated with immunotherapy (cohort 2). Here, we report results from cohort 1 of this clinical trial.
METHODS: LITESPARK-003 is an open-label, single-arm, phase 2 study at ten hospitals and cancer centres in the USA. In cohort 1, eligible patients were at least 18 years of age, had an Eastern Cooperative Oncology Group performance status of 0 or 1, and had received no previous systemic therapy for locally advanced or metastatic renal cell carcinoma. Patients received belzutifan 120 mg orally once daily and cabozantinib 60 mg orally once daily until unacceptable adverse events, disease progression, or patient withdrawal. The primary endpoint was investigator-assessed confirmed objective response according to Response Evaluation Criteria in Solid Tumors version 1.1. Antitumour activity and safety were assessed in all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT03634540, and is ongoing.
FINDINGS: Between Sept 27, 2018, and Jan 10, 2023, we screened 138 patients for eligibility, and 50 (36%) were enrolled and assigned to cohort 1. The median age was 64 years (IQR 57-72). 40 (80%) of 50 patients were male and ten (20%) were female. 48 (96%) patients were White, one (2%) patient was Black or African American, and one (2%) was of a race in the other category. As of the data cutoff (May 15, 2023), median follow-up was 24·3 months (IQR 13·9-32·0). 35 (70%, 95% CI 55-82) of 50 patients had a confirmed objective response, including four (8%) who had a complete response and 31 (62%) who had a partial response. The most frequent grade 3-4 treatment-related adverse events were hypertension (six [12%] patients), anaemia (five [10%] patients), and fatigue (four [8%] patients). Seven (14%) of 50 patients had serious treatment-related adverse events. No treatment-related deaths occurred.
INTERPRETATION: Belzutifan plus cabozantinib has promising antitumour activity in treatment-naive patients with advanced clear-cell renal cell carcinoma and further investigation of an HIF-2? inhibitor in combination with a multitargeted tyrosine kinase inhibitor as a treatment option in this population is warranted.
FUNDING: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc, Rahway, NJ, USA, and the National Cancer Institute.
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Nature
Crypt Density and Recruited Enhancers Underlie Intestinal Tumour Initiation
Gaynor L, Singh H, Tie G, Badarinath K, Madha S, Bhattacharya S, Murata K, Jadhav U, Shivdasani RA
Oncogenic mutations that drive colorectal cancer can be present in healthy intestines for long periods without overt consequence1,2. Mutation of Adenomatous polyposis coli (Apc), the most common initiating event in conventional adenomas3, activates Wnt signalling, hence conferring fitness on mutant intestinal stem cells (ISCs)4,5. Apc mutations may occur in ISCs that arose by routine self-renewal or by dedifferentiation of their progeny. Although ISCs of these different origins are fundamentally similar6,7, it is unclear if both generate tumours equally well in uninjured intestines. Also unknown is whether cis-regulatory elements are substantively modulated upon Wnt hyperactivation or as a feature of subsequent tumours. Here, we show in two mouse models that adenomas are not an obligatory outcome of Apc deletion in either ISC source but require proximity of mutant intestinal crypts. Reduced crypt density abrogates, and aggregation of mutant colonic crypts augments, adenoma formation. Moreover, adenoma-resident ISCs open chromatin at thousands of enhancers that are inaccessible in Apc-null ISCs not associated with adenomas. These cis-elements explain adenoma-selective gene activity and persist, with little further expansion of the repertoire, as other oncogenic mutations accumulate. Thus, cooperativity between neighbouring mutant crypts and new accessibility at specific enhancers are key steps early in intestinal tumourigenesis.
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Nature Cell Biology
Chaperone-Mediated Insertion of Mitochondrial Import Receptor TOM70 Protects Against Diet-Induced Obesity
Latorre-Muro P, Vitale T, Ravichandran M, Zhang K, Palozzi JM, Bennett CF, Lamas-Paz A, Sohn JH, Jackson TD, Jedrychowski M, Gygi SP, Kajimura S, Schmoker A, Jeon H, Eck MJ, Puigserver P
Outer mitochondrial membrane (OMM) proteins communicate with the cytosol and other organelles, including the endoplasmic reticulum. This communication is important in thermogenic adipocytes to increase the energy expenditure that controls body temperature and weight. However, the regulatory mechanisms of OMM protein insertion are poorly understood. Here the stress-induced cytosolic chaperone PPID (peptidyl-prolyl isomerase D/cyclophilin 40/Cyp40) drives OMM insertion of the mitochondrial import receptor TOM70 that regulates body temperature and weight in obese mice, and respiratory/thermogenic function in brown adipocytes. PPID PPIase activity and C-terminal tetratricopeptide repeats, which show specificity towards TOM70 core and C-tail domains, facilitate OMM insertion. Our results provide an unprecedented role for endoplasmic-reticulum-stress-activated chaperones in controlling energy metabolism through a selective OMM protein insertion mechanism with implications in adaptation to cold temperatures and high-calorie diets.
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Nature Communications
Deeper Response Predicts Better Outcomes in High-Risk-Smoldering-Myeloma: Results of the I-PRISM Phase II Clinical Trial
Nadeem O, Aranha MP, Redd R, Timonian M, Magidson S, Lightbody ED, Alberge JB, Bertamini L, Dutta AK, El-Khoury H, Bustoros M, Laubach JP, Bianchi G, O'Donnell E, Wu T, Tsuji J, Anderson KC, Getz G, Trippa L, Richardson PG, Sklavenitis-Pistofidis R, Ghobrial IM
Early therapeutic intervention in high-risk smoldering multiple myeloma (HR-SMM) has shown benefits, however, no studies have assessed whether biochemical progression or response depth predicts long-term outcomes. The single-arm I-PRISM phase II trial (NCT02916771) evaluated ixazomib, lenalidomide, and dexamethasone in 55 patients with HR-SMM. The primary endpoint, median progression-free survival (PFS), was not reached (NR) (95% CI: 57.7-NR, median follow-up 50 months). The secondary endpoint, biochemical PFS, was 48.6 months (95% CI: 39.9-NR) and coincided with or preceded SLiM-CRAB in eight patients. For additional secondary objectives, the overall response rate was 93% with 31% achieving complete response (CR) and 45% very good partial response (VGPR) or better. CR correlated strongly with the absence of SLiM-CRAB and biochemical progression. MRD-negativity (10-5 sensitivity) predicted a 5-year biochemical PFS of 100% versus 40% in MRD-positive patients (p?=?0.051), demonstrating that deep responses significantly improve time to progression. Exploratory single-cell RNA sequencing linked tumor MHC class I expression to proteasome inhibitor response, and a lower proportion of GZMB+?T cells within clonally expanded CD8+?T cells associated with suboptimal outcomes.
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Nature Communications
Intratumor Heterogeneity of EGFR Expression Mediates Targeted Therapy Resistance and Formation of Drug Tolerant Microenvironment
Son J, Li J, Lopez T, Eser PÖ, Ogino A, Eum Y, Thai T, Feng WW, Eschle BK, Poitras MJ, Barbie D, Gokhale P, Jänne PA, Haikala HM
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors are commonly used to treat non-small cell lung cancers with EGFR mutations, but drug resistance often emerges. Intratumor heterogeneity is a known cause of targeted therapy resistance and is considered a major factor in treatment failure. This study identifies clones of EGFR-mutant non-small cell lung tumors expressing low levels of both wild-type and mutant EGFR protein. These EGFR-low cells are intrinsically more tolerant to EGFR inhibitors, more invasive, and exhibit an epithelial-to-mesenchymal-like phenotype compared to their EGFR-high counterparts. The EGFR-low cells secrete Transforming growth factor beta (TGF?) family cytokines, leading to increased recruitment of cancer-associated fibroblasts and immune suppression, thus contributing to the drug-tolerant tumor microenvironment. Notably, pharmacological induction of EGFR using epigenetic inhibitors sensitizes the resistant cells to EGFR inhibition. These findings suggest that intrinsic drug resistance can be prevented or reversed using combination therapies.
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Science
Rare Germline Structural Variants Increase Risk for Pediatric Solid Tumors
Gillani R, Collins RL, Crowdis J, Garza A, Jones JK, Walker M, Sanchis-Juan A, Whelan CW, Pierce-Hoffman E, Talkowski ME, Brand H, Haigis K, LoPiccolo J, AlDubayan SH, Gusev A, Crompton BD, Janeway KA, Van Allen EM
Pediatric solid tumors are a leading cause of childhood disease mortality. In this work, we examined germline structural variants (SVs) as risk factors for pediatric extracranial solid tumors using germline genome sequencing of 1765 affected children, their 943 unaffected parents, and 6665 adult controls. We discovered a sex-biased association between very large (>1 megabase) germline chromosomal abnormalities and increased risk of solid tumors in male children. The overall impact of germline SVs was greatest in neuroblastoma, where we uncovered burdens of ultrarare SVs that cause loss of function of highly expressed, mutationally constrained genes, as well as noncoding SVs predicted to disrupt chromatin domain boundaries. Collectively, we estimate that rare germline SVs explain 1.1 to 5.6% of pediatric cancer liability, establishing them as an important component of disease predisposition.
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Blood Advances
Nivolumab to Restore T-Cell Fitness in CAR-T Refractory Multiple Myeloma
Waldschmidt JM, Sotudeh N, Arora S, Vijaykumar T, Anand P, Stuart H, Frede J, Munshi NCAnderson KC, Yee AJ, Knoechel B, Lohr JG, Raje NS
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Cancer
Generative Artificial Intelligence as a Source of Breast Cancer Information for Patients: Proceed with Caution
Park KU, Lipsitz S, Dominici LS, Lynce F, Minami CA, Nakhlis F, Waks AG, Warren LE, Weissman JS, King TA, Mittendorf EA
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Cancer Immunology Research
A Phase I Trial of Trebananib, an Angiopoietin 1 and 2 Neutralizing Peptibody, Combined with Pembrolizumab in Patients with Advanced Ovarian and Colorectal Cancer
Huffman BM, Rahma OE, Tyan K, Li YY, Giobbie-Hurder A, Schlechter BL, Bockorny B, Manos MP, Cherniack AD, Baginska J, Mariño-Enríquez A, Kao KZ, Maloney AK, Ferro A, Kelland S, Ng K, Singh H, Welsh EL, Pfaff KL, Giannakis M, Rodig SJ, Hodi FS, Cleary JM
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Clinical Cancer Research
A Translational Study of the ATR Inhibitor Berzosertib as Monotherapy in Four Molecularly Defined Cohorts of Advanced Solid Tumors
Cote GM, Kochupurakkal BS, Do K, Bullock A, Cheng ML, Muzikansky A, McLoughlin DE, Cleary JM, Gao X, Parikh A, Park JC, Weekes CD, Yeku O, Zou L, Shapiro GI
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Clinical Chemistry
Impact of Higher Cell-Free DNA Yields on Liquid Biopsy Testing in Glioblastoma Patients
Iorgulescu JB, Blewett T, Xiong K, Crnjac A, Liu R, Sridhar S, Braun DA, Sellars MC, Cheng J, Rhoades J, Reardon DA, Makrigiorgos GM, Wu CJ, Adalsteinsson VA
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Lancet Digital Health
A Prospectively Deployed Deep Learning-Enabled Automated Quality Assurance Tool for Oncological Palliative Spine Radiation Therapy
Kehayias CE, Bontempi D, Quirk S, Friesen S, Bredfeldt J, Kosak T, Kearney M, Tishler R, Pashtan I, Huynh MA, Aerts HJWL, Mak RH, Guthier CV
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Neuro-Oncology
Analysis of HER2 Expression Changes from Breast Primary to Brain Metastases and the Impact of HER2-Low Expression on Overall Survival
Pereslete AM, Hughes ME, Martin AR, Files J, Nguyen K, Buckley L, Patel A, Moore A, Winer EP, Dillon D, Li T, Tolaney SM, Lin NU, Sammons SL
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Neuro-Oncology
Multimodal Deep Learning Improves Recurrence Risk Prediction in Pediatric Low-Grade Gliomas
Mahootiha M, Tak D, Ye Z, Zapaishchykova A, Likitlersuang J, Climent Pardo JC, Boyd A, Chopra R, Prabhu SP, Liu KX, Elhalawani H, Aerts HJWL, Bandopadhayay P, Ligon KL, Haas-Kogan D, Poussaint TY, Kann BH
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