Previous FY22 Awardees
September - November 2021
Joe Y. Chang, M.D., Ph.D., FASTRO & Jack A. Roth, M.D., F.A.C.S.
The Lancet Oncology
Stereotactic ablative radiotherapy for operable stage I non-small-cell lung cancer (revised STARS): long-term results of a single-arm, prospective trial with prespecified comparison to surgery
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Mariana Chavez Mac Gregor, M.D., MSc & Sharon Hermes Giordano, M.D., M.P.H.
JAMA Oncology
Evaluation of COVID-19 mortality and adverse outcomes in US patients with or without cancer
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Courtney DiNardo, M.D., Curtis Lachowiez, M.D., Marina Konopleva, M.D., Ph.D., & Hagop M. Kantarjian, M.D.
Journal of Clinical Oncology
Venetoclax combined with FLAG-IDA induction and consolidation in newly diagnosed and relapsed or refractory Acute Myeloid Leukemia
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Ansam Sinjab Fayed, Ph.D., Guangchun Han, Ph.D., Linghua Wang, M.D., Ph.D., Humam Kadara, Ph.D.
Cancer Discovery
Resolving the spatial and cellular architecture of lung adenocarcinoma by multiregion single-cell sequencing
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I-Lin Ho, Ph.D. & Andrea Viale, M.D.
Science
Epithelial memory of inflammation limits tissue damage while promoting pancreatic tumorigenesis
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Eric Jonasch, M.D.
The New England Journal of Medicine
Belzutifan for renal cell carcinoma in von Hippel–Lindau Disease
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Amanda L. Olson, M.D., Ruitao Lin, Ph.D., David Marin, M.D, Katy Rezvani, M.D., Ph.D.
Journal of Clinical Oncology
Third-party BK virus-specific cytotoxic T lymphocyte therapy for hemorrhagic cystitis following allotransplantation
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Kanwal Pratap Singh Raghav, M.B.B.S. & Daniel Halperin, M.D.
Cancer Discovery
Efficacy, safety, and biomarker analysis of combined PD-L1 (Atezolizumab) and VEGF (Bevacizumab) blockade in advanced malignant peritoneal mesothelioma
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Andrea Viale, M.D. & Giulio Draetta, M.D., Ph.D.
Cancer Discovery
Medium-chain Acyl-CoA dehydrogenase protects mitochondria from lipid peroxidation in glioblastoma
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Joe Y. Chang, M.D., Ph.D., FASTRO & Jack A. Roth, M.D., F.A.C.S.
Stereotactic ablative radiotherapy for operable stage I non-small-cell lung cancer (revised STARS): long-term results of a single-arm, prospective trial with prespecified comparison to surgery
Background
A previous pooled analysis of the STARS and ROSEL trials showed higher survival af-ter stereotactic ablative radiotherapy (SABR) than with surgery for operable early-stage non-small-cell lung cancer (NSCLC), but that analysis had notable limitations. This study reports long-term results of the revised STARS trial, in which the SABR group was re-accrued with a larger sample size, along with a protocol-specified propensity-matched comparison with a prospectively registered, contemporary institutional cohort of patients who underwent video-assisted thoracoscop-ic surgical lobectomy with mediastinal lymph node dissection (VATS L-MLND).
Findings
Between Sept 1, 2015, and Jan 31, 2017, 80 patients were enrolled and included in effi-cacy and safety analyses. Median follow-up time was 5·1 years (IQR 3·9–5·8). Overall survival was 91% (95% CI 85–98) at 3 years and 87% (79–95) at 5 years. SABR was toler-ated well, with no grade 4–5 toxicity and one (1%) case each of grade 3 dyspnoea, grade 2 pneumonitis, and grade 2 lung fibrosis. No serious adverse events were recorded. Over-all survival in the propensity-matched VATS L-MLND cohort was 91% (95% CI 85–98) at 3 years and 84% (76–93) at 5 years. Non-in-feriority was claimed since the 3-year overall survival after SABR was not lower than that observed in the VATS L-MLND group. There was no significant difference in overall surviv-al between the two patient cohorts (hazard ratio 0·86 [95% CI 0·45–1·65], p=0·65) from a multivariable analysis.
Interpretation
Long-term survival after SABR is non-infe-rior to VATS L-MLND for operable stage IA NSCLC. SABR remains promising for such cases but multidisciplinary management is strongly recommended.
Joe Y Chang, Reza J Mehran , Lei Feng, Vivek Verma, Zhongxing Liao , James W Welsh, Steven H Lin , Michael S O’Reilly, Melenda D Jeter, Peter A Balter, Stephen E McRae, Donald Berry, John V Heymach, Jack A Roth, on behalf of The STARS Lung Cancer Trials Group
Professor, Department of Radiation Oncology
Director, Body Stereotactic Program
Texas 4000 Distinguished Professorship
Professor, Department of Thoracic & Cardiovascular Surgery
Director, W.M. Keck Center for Innovative Cancer Therapies
Chief, Section of Thoracic Molecular Oncology
Bud S. Johnson Distinguished Clinical Chair Emeritus
Mariana Chavez Mac Gregor, M.D., MSc & Sharon Hermes Giordano, M.D., M.P.H.
Associate Professor, Departments of Health Services Research & Breast Medical Oncology
Chair, Department of Health Services Research
Professor, Departments of Health Services Research & Breast Medical Oncology
Colin Powell Chair for Cancer Research
Evaluation of COVID-19 mortality and adverse outcomes in US patients with or without cancer
Importance
As the COVID-19 pandemic con-tinues, understanding the clinical outcomes of patients with cancer and COVID-19 has be-come critically important.
Objective
To compare the outcomes of pa-tients with or without cancer who were diag-nosed with COVID-19 and to identify the fac-tors associated with mortality, mechanical ventilation, intensive care unit (ICU) stay, and hospitalization.
Main Outcomes and Measures
Mortality, me-chanical ventilation, ICU stay, and hospitaliza-tion within 30 days of COVID-19 diagnosis were the main outcomes. Unadjusted rates and ad-justed odds ratios (ORs) of adverse outcomes were presented according to exposure group.
Results
A total of 507 307 patients with COVID-19 were identified (mean [SD] age, 48.4 [18.4] years; 281 165 women [55.4%]), of whom 493 020 (97.2%) did not have cancer. Among the 14 287 (2.8%) patients with cancer, 9991 (69.9%) did not receive recent treatment and 4296 (30.1%) received recent treatment. In unadjusted analyses, patients with cancer, regardless of recent treatment received, were more likely to have adverse outcomes com-pared with patients without cancer (eg, mortality rate: 1.6% for patients without cancer, 5.0% for patients with no recent cancer treatment, and 7.8% for patients with recent cancer treatment). After adjustment, patients with no recent can-cer treatment had similar or better outcomes than patients without cancer (eg, mortality OR, 0.93 [95% CI, 0.84-1.02]; mechanical venti-lation OR, 0.61 [95% CI, 0.54-0.68]). In con-trast, a higher risk of death (OR, 1.74; 95% CI, 1.54-1.96), ICU stay (OR, 1.69; 95% CI, 1.54-1.87), and hospitalization (OR, 1.19; 95% CI, 1.11-1.27) was observed in patients with recent cancer treatment. Compared with patients with nonmetastatic solid tumors, those with meta-static solid tumors and hematologic malignant neoplasms had worse outcomes (eg, mortal-ity OR, 2.36 [95% CI, 1.96-2.84]; mechanical ventilation OR, 0.87 [95% CI, 0.70-1.08]). Re-cent chemotherapy and chemoimmunothera-py were also associated with worse outcomes (eg, chemotherapy mortality OR, 1.84 [95% CI, 1.51-2.26]).
Conclusions and Relevance
This cohort study found that patients with recent cancer treatment and COVID-19 had a significantly higher risk of adverse outcomes, and patients with no recent cancer treatment had similar outcomes to those without cancer. The find-ings have risk stratification and resource use implications for patients, clinicians, and health systems.
Mariana Chavez-Macgregor, Xiudong Lei, Hui Zhao , Paul Scheet , Sharon H. Giordano
Courtney DiNardo, M.D., Curtis Lachowiez, M.D., Marina Konopleva, M.D., Ph.D., & Hagop M. Kantarjian, M.D.
Venetoclax combined with FLAG-IDA induction and consolidation in newly diagnosed and relapsed or refractory Acute Myeloid Leukemia
Purpose
Sixty percent of newly diagnosed patients with acute myeloid leukemia (ND-AML) receiving front-line therapy attain a complete response (CR), yet 30%-40% of patients relapse. Relapsed or refrac-tory AML (R/R-AML) remains a particularly adverse population necessitating improved therapeutic op-tions. This phase Ib/II study evaluated the safety and efficacy of fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin combined with the B-cell lymphoma-2 inhibitor venetoclax in ND-AML and R/R-AML.
Materials and Methods
The phase IB portion (PIB) enrolled patients with R/R-AML using a 3 + 3 dose escalation and de-es-calation algorithm for identification of maximum tol-erated dose and dose-limiting toxicities. The phase II portion enrolled patients into two arms to evaluate response and time-to-event end points: phase IIA (PIIA): ND-AML and phase IIB (PIIB): R/R-AML.
Results
Sixty-eight patients have enrolled to date (PIB, 16; PIIA, 29; PIIB, 23). Median age was 46 years (range, 20-73). Grade 3 and 4 adverse events oc-curring in ≥ 10% of patients included febrile neutro-penia (50%), bacteremia (35%), pneumonia (28%), and sepsis (12%). The overall response rate for PIB, PIIA, and PIIB was 75%, 97%, and 70% with 75%, 90%, and 61%, respectively, achieving a com-posite CR. Measurable residual disease–negative composite CR was attained in 96% of ND-AML and 69% of R/R-AML patients. After a median follow-up of 12 months, median overall survival (OS) for both PII cohorts was not reached. Fifty-six percent of patients proceeded to allogeneic hematopoietic stem-cell transplantation (ND-AML, 69%; R/R-AML, 46%). In R/R-AML, allogeneic hematopoietic stem-cell transplantation resulted in a significant improve-ment in OS (median OS, NR; 1-year OS, 87%). One-year survival post-HSCT was 94% in ND-AML and 78% in R/R-AML.
Conclusion
Fludarabine, cytarabine, granulocyte colony-stimu-lating factor, and idarubicin + venetoclax represents an effective intensive treatment regimen in ND-AML and R/R-AML patients, associated with deep re-missions and a high rate of transition to successful transplantation.
Courtney D. DiNardo, Curtis A. Lachowiez, Koichi Takahashi , Sanam Loghavi , Lianchun Xiao, Tapan Kadia , Naval Daver , Maria Adeoti, Nicholas J. Short , Koji Sasaki , Sa Wang , Gautam Borthakur , Ghayas Issa , Abhishek Maiti , Yesid Alvarado , Naveen Pemmaraju , Guillermo Montalban Bravo , Lucia Masarova , Musa Yilmaz , Nitin Jain, Michael Andreeff , Elias Jabbour , Guillermo Garcia-Manero , Steven Kornblau , Farhad Ravandi , Marina Y. Konopleva , Hagop M. Kantarjian
Associate Professor, Department of Leukemia
Associate Chair, Institutional Review Board
Fellow, Department of Cancer Medicine
Deputy Chair, Department of Leukemia
Professor, Departments of Leukemia & Stem Cell Transplantation
Frances King Black Memorial Professorship for Cancer Research
Chair and Professor, Department of Leukemia
Associate Vice President, Global Oncology Research
Samsung Distinguished University Chair in Cancer Medicine
Ansam Sinjab Fayed, Ph.D., Guangchun Han, Ph.D., Linghua Wang, M.D., Ph.D., Humam Kadara, Ph.D.
Postdoctoral Fellow, Department of Translational Molecular Pathology
Postdoctoral Fellow, Department of Genomic Medicine
Assistant Professor, Department of Genomic Medicine
Associate Professor, Department of Translational Molecular Pathology
Resolving the spatial and cellular architecture of lung adenocarcinoma by multiregion single-cell sequencing
Little is known of the geospatial architecture of individual cell populations in lung adenocarcinoma (LUAD) evolution. Here, we perform single-cell RNA sequencing of 186,916 cells from five early-stage LUADs and 14 multiregion normal lung tissues of defined spatial proximities from the tumors. We show that cellular lineages, states, and transcriptomic features geospatially evolve across normal regions to LUADs. LUADs also exhibit pronounced intratumor cell heterogeneity within single sites and transcriptional lineage-plasticity programs. T regulatory cell phenotypes are increased in normal tissues with proximity to LUAD, in contrast to diminished signatures and fractions of cytotoxic CD8+ T cells, antigen-presenting macrophages, and inflammatory dendritic cells. We further find that the LUAD ligand-receptor interactome harbors increased expression of epithelial CD24, which mediates protumor phenotypes. These data provide a spatial atlas of LUAD evolution, and a resource for identification of targets for its treatment. SIGNIFICANCE: The geospatial ecosystem of the peripheral lung and early-stage LUAD is not known. Our multiregion single-cell sequencing analyses unravel cell populations, states, and phenotypes in the spatial and ecologic evolution of LUAD from the lung that comprise high-potential targets for early interception.
Significance: The geospatial ecosystem of the periph-eral lung and early-stage LUAD is not known. Our multiregion single-cell se-quencing analyses unravel cell popula-tions, states, and phenotypes in the spa-tial and ecologic evolution of LUAD from the lung that comprise high-potential tar-gets for early interception.
Ansam Sinjab, Guangchun Han, Warapen Treekitkarnmongkol, Kieko Hara, Patrick M. Brennan, Minghao Dang, Dapeng Hao, Ruiping Wang, Enyu Dai, Hitoshi Dejima, Jiexin Zhang, Elena Bogatenkova, Beatriz Sanchez-Espiridion, Kyle Chang, Danielle R. Little, Samer Bazzi, Linh M. Tran, Kostyantyn Krysan, Carmen Behrens, Dzifa Y. Duose, Edwin R. Parra, Maria Gabriela Raso, Luisa M. Solis, Junya Fukuoka, Jianjun Zhang, Boris Sepesi, Tina Cascone, Lauren Averett Byers, Don L. Gibbons, Jichao Chen, Seyed Javad Moghaddam, Edwin J. Ostrin, Daniel Rosen, John V. Heymach, Paul Scheet, Steven M. Dubinett, Junya Fujimoto, Ignacio I. Wistuba, Christopher S. Stevenson, Avrum Spira, Linghua Wang, Humam Kadara
I-Lin Ho, Ph.D. & Andrea Viale, M.D.
Epithelial memory of inflammation limits tissue damage while promoting pancreatic tumorigenesis
Introduction
The association between tumors and inflammation is a long-established clinical ob-servation. Although many studies have demonstrat-ed that the inflammatory microenvironment can pro-mote tumor growth through the activation of survival and proliferation programs in cancer cells, the rea-son why inflammation, an evolutionarily conserved response to damage aimed at reestablishing tissue integrity upon injury, might be integral to tumorigen-esis remains unknown.
Results
By investigating the effects of inflamma-tion on normal pancreatic epithelial cells in differ-ent mouse models, we discovered that long after the complete resolution, a transient inflammatory event primes pancreatic epithelial cells to cooperate with oncogenic Kras to induce pancreatic tumors. Indeed, upon recovery from a single acute inflam-mation, epithelial pancreatic cells display an endur-ing adaptive response associated with sustained transcriptional and epigenetic reprogramming that leads to the activation of multiple gene expression programs, including embryonic programs activated during cancer progression. While promoting tumor development, such adaptation to tissue damage facilitates the prompt acquisition of acinar-to-ductal metaplasia upon subsequent inflammatory events. This rapid dedifferentiation program of acinar cells, that lasts for the length of the stimulus and from which the tissue promptly and apparently complete-ly recovers, represents a physiological mechanism for limiting tissue damage through the rapid de-crease of zymogen production that would otherwise fuel further damage and inflammation. As a result, pancreatic tissues exposed to initial inflammation undergo a markedly attenuated response and lim-ited tissue damage to subsequent inflammatory episodes. Because metaplastic lesions are medi-ated by the activation of mitogen-activated protein kinase (MAPK) signaling, we demonstrate that acti-vating mutations of Kras, maintaining an irreversible acinar-to-ductal metaplasia through MAPK constitu-tive signaling, are protective against tissue damage induced by pancreatic inflammation.
Conclusion
We have uncovered a new physi-ologic role of somatic mutations in preserving tis-sue homeostasis during repeated damages. We propose that KRAS mutations, independent from the eventual contribution to tumorigenesis, may be beneficial and under strong positive selection in the context of recurrent pancreatitis, perhaps repre-senting a nearly universal event in the development of pancreatic cancer.
Edoardo Del Poggetto, I. Lin Ho, Chiara Balestrieri, Er Yen Yen, Shaojun Zhang, Francesca Citron, Rutvi Shah, Denise Corti, Giuseppe R. Diaferia, Chieh Yuan Li, Sara Loponte, Federica Carbone, Yoku Hayakawa, Giovanni Valenti, Shan Jiang, Luigi Sapio, Hong Jiang, Prasenjit Dey, Sisi Gao, Angela K. Deem, Stefan Rose-John, Wantong Yao, Haoqiang Ying, Andrew D. Rhim, Giannicola Genovese, Timothy P. Heffernan, Anirban Maitra, Timothy C. Wang, Linghua Wang, Giulio F. Draetta, Alessandro Carugo, Gioacchino Natoli, Andrea Viale
Postdoctoral Fellow, Department of Genomic Medicine
Assistant Professor, Department of Genomic Medicine
Eric Jonasch, M.D.
Professor, Department of Genitourinary Medical Oncology
Belzutifan for Renal Cell Carcinoma in von Hippel–Lindau Disease
Background
Patients with von Hippel–Lindau (VHL) disease have a high incidence of renal cell carcinoma owing to VHL gene inactivation and constitutive activation of the transcription factor hypoxia-in-ducible factor 2α (HIF-2α).
Methods
In this phase 2, open-label, single-group trial, we investigated the efficacy and safety of the HIF-2αinhibitor belzutifan (MK-6482, previously called PT2977), administered orally at a dose of 120 mg daily, in patients with renal cell carcinoma associ-ated with VHL disease. The primary end point was objective response (complete or partial response) as measured according to the Response Evalua-tion Criteria in Solid Tumors, version 1.1, by an independent central radiology review committee. We also assessed responses to belzutifan in pa-tients with non–renal cell carcinoma neoplasms and the safety of belzutifan.
Results
After a median follow-up of 21.8 months (range, 20.2 to 30.1), the percentage of patients with renal cell carcinoma who had an objective re-sponse was 49% (95% confidence interval, 36 to 62). Responses were also observed in patients with pancreatic lesions (47 of 61 patients [77%]) and central nervous system hemangioblastomas (15 of 50 patients [30%]). Among the 16 eyes that could be evaluated in 12 patients with ret-inal hemangioblastomas at baseline, all (100%) were graded as showing improvement. The most common adverse events were anemia (in 90% of the patients) and fatigue (in 66%). Seven patients discontinued treatment: four patients voluntarily discontinued, one discontinued owing to a treat-ment-related adverse event (grade 1 dizziness), one discontinued because of disease progression as assessed by the investigator, and one patient died (of acute toxic effects of fentanyl).
Conclusions
Belzutifan was associated with predominantly grade 1 and 2 adverse events and showed ac-tivity in patients with renal cell carcinomas and non–renal cell carcinoma neoplasms associated with VHL disease. (Funded by Merck Sharp and Dohme and others; MK-6482-004 ClinicalTrials.gov number, NCT03401788.)
Eric Jonasch, M.D., Frede Donskov, M.D., Ph.D., Othon Iliopoulos, M.D., W. Kimryn Rathmell, M.D., Ph.D., Vivek K. Narayan, M.D., Benjamin L. Maughan, M.D., Stephane Oudard, M.D., Tobias Else, M.D., Jodi K. Maranchie, M.D., Sarah J. Welsh, M.D., Sanjay Thamake, Ph.D., Eric K. Park, M.D., et al., for the MK-6482-004 Investigators
Amanda L. Olson, M.D., Ruitao Lin, Ph.D., David Marin, M.D, Katy Rezvani, M.D., Ph.D.
Third-party BK virus-specific cytotoxic T lymphocyte therapy for hemorrhagic cystitis following allotransplantation
Purpose
BK virus-associated hemorrhagic cystitis (BKV-HC) is a common complication of al-logenic hematopoietic stem cell transplanta-tion (AHSCT), particularly in recipients of al-ternative donor transplants, which are being performed in increasing numbers. BKV-HC typically results in painful hematuria, urinary obstruction, and renal dysfunction, without a definitive therapeutic option.
Methods
We performed a clinical trial (ClinicalTrials.gov identifier: NCT02479698) to assess the feasibility, safety, and efficacy of adminis-tering most closely HLA-matched third-par-ty BKV-specific cytotoxic T lymphocytes (CTLs), generated from 26 healthy donors and banked for off-the-shelf use. The cells were infused into 59 patients who developed BKV-HC following AHSCT. Comprehensive clinical assessments and correlative studies were performed.
Results
Response to BKV-CTL infusion was rapid; the day 14 overall response rate was 67.7% (40 of 59 evaluable patients), which increased to 81.6% among evaluable patients at day 45 (40 of 49 evaluable patients). No patient lost a previously achieved response. There were no cases of de novo grade 3 or 4 graft-ver-sus-host disease, graft failure, or infusion-re-lated toxicities. BKV-CTLs were identified in patient blood samples up to 3 months post-infusion and their in vivo expansion predicted for clinical response. A matched-pair analy-sis revealed that, compared with standard of care, after accounting for prognostic covari-ate effects, treatment with BKV-CTLs result-ed in higher probabilities of response at all follow-up timepoints as well as significantly lower transfusion requirement.
Conclusion
Off-the-shelf BKV-CTLs are a safe and effec-tive therapy for the management of patients with BKV-HC after AHSCT.
Amanda Olson, Ruitao Lin , David Marin , Hind Rafei , Mustafa H. Bdaiwi, Peter F. Thall , Rafet Basar , Ala Abudayyeh , Pinaki Prosad Banerjee , Fleur M. Aung , Indresh Kaur, Glorette Abueg, Sheetal Rao, Roy Chemaly , Victor Mulanovich , Gheath Al-Atrash , Amin M. Alousi , Borje S. Andersson, Paolo Anderlini , Qaiser Bashir, Karla M. Castro, May Daher , Isabel M. Galvan, Chitra Hosing , Jin S. Im , Roy B. Jones, Partow Kebriaei , Issa Khouri , Rohtesh Mehta , Jeffrey Molldrem , Yago Nieto , Betul Oran , Uday Popat , Muzaffar Qazilbash , Gabriela Rondon , Neeraj Saini , Bryan Spencer, Samer Srour , Dominique Washington, Melissa Barnett, Richard E. Champlin , Elizabeth J. Shpall , Katayoun Rezvani
Associate Professor, Department Stem Cell Transplantation
Assistant Professor, Department of Biostatistics
Professor, Department of Stem Cell Transplantation
Professor, Department of Stem Cell Transplantation
Director, Translational Research Medical Director, GMP Cell Therapy Laboratory
Director, Cellular Therapy
Sally Cooper Murray Chair in Cancer Research
Kanwal Pratap Singh Raghav, M.B.B.S. & Daniel Halperin, M.D.
Associate Professor, Department of GI Medical Oncology
Clinical Medical Director, Ambulatory Treatment Center
Associate Professor, Department of GI Medical Oncology
Clinical Medical Director, Gastrointestinal Center
Efficacy, safety, and biomarker analysis of combined PD-L1 (Atezolizumab) and VEGF (Bevacizumab) blockade in advanced malignant peritoneal mesothelioma
Malignant peritoneal mesothelioma (MPeM) is a rare but aggressive malignancy with limited treatment options. VEGF inhibition enhances efficacy of immune-checkpoint inhibitors by reworking the immunosuppressive tumor milieu. Efficacy and safety of com¬bined PD-L1 (atezolizumab) and VEGF (bevacizumab) blockade (AtezoBev) was assessed in 20 patients with advanced and unresectable MPeM with progression or intolerance to prior platinum-pemetrexed chemotherapy. The primary endpoint of confirmed objective response rate per RECISTvl.1 by independ¬ent radiology review was 40% [8/20; 95% confidence interval (CI), 19.1-64.0] with median response duration of 12.8 months. Six (75%) responses lasted for >10 months. Progression-free and overall survival at one year were 61% (95% CI, 35-80) and 85% (95% CI, 60-95), respectively. Responses occurred notwithstanding low tumor mutation burden and PD-L1 expression status. Baseline epithelial- mesenchymal transition gene expression correlated with therapeutic resistance/response (r = 0.80; P = 0.0010). AtezoBev showed promising and durable efficacy in patients with advanced MPeM with an acceptable safety profile, and these results address a grave unmet need for this orphan disease.
Significance: Efficacy of atezolizumab and bevacizumab vis-à-vis response rates and survival in ad-vanced peritoneal mesothelioma previously treated with chemotherapy surpassed out-comes expected with conventional thera-pies. Biomarker analyses uncovered epi-thelial–mesenchymal transition phenotype as an important resistance mechanism and showcase the value and feasibility of per-forming translationally driven clinical trials in rare tumors.
Kanwal Raghav, Suyu Liu, Michael J. Overman, Anneleis F. Willett, Mark Knafl, Szu Chin Fu, Anais Malpica, Seema Prasad, Richard E Royal, Christopher P. Scally, Paul F. Mansfield, Ignacio I. Wistuba, Andrew P. Futreal, Dipen M. Maru, Luisa M. Solis Soto, Edwin R. Parra Cuentas, Honglei Chen, Pamela Villalobos, Anuj Verma, Armeen Mahvash, Patrick Hwu, Patricia Cortazar, Edward McKenna, Cindy Yun, Shannon Dervin, Katja Schulze, Walter C. Darbonne, Ajaykumar C. Morani, Scott Kopetz, Keith F. Fournier, Scott E. Woodman, James C. Yao, Gauri R. Varadhachary, Daniel M. Halperin
Andrea Viale, M.D. & Giulio Draetta, M.D., Ph.D.
Medium-chain Acyl-CoA dehydrogenase protects mitochondria from lipid peroxidation in glioblastoma
Glioblastoma (GBM) is highly resistant to chemotherapies, immune-based therapies, and targeted inhibitors. To identify novel drug targets, we screened orthotopically implanted, patient-derived glioblastoma sphere-forming cells using an RNAi library to probe essential tumor cell metabolic programs. This identified high dependence on mitochondrial fatty acid metabolism. We focused on medium-chain acyl-CoA dehydrogenase (MCAD), which oxidizes mediumchain fatty acids (MCFA), due to its consistently high score and high expression among models and upregulation in GBM compared with normal brain. Beyond the expected energetics impairment, MCAD depletion in primary GBM models induced an irreversible cascade of detrimental metabolic effects characterized by accumulation of unmetabolized MCFAs, which induced lipid peroxidation and oxidative stress, irreversible mitochondrial damage, and apoptosis. Our data uncover a novel protective role for MCAD to clear lipid molecules that may cause lethal cell damage, suggesting that therapeutic targeting of MCFA catabolism may exploit a key metabolic feature of GBM.
Significance: MCAD exerts a protective role to prevent accumulation of toxic metabolic by-prod-ucts in glioma cells, actively catabolizing lipid species that would otherwise affect mitochondrial integrity and induce cell death. This work represents a first demon-stration of a nonenergetic role for depen-dence on fatty acid metabolism in cancer.
Francesca Puca, Fei Yu, Caterina Bartolacci, Piergiorgio Pettazzoni, Alessandro Carugo, Emmet Huang-Hobbs, Jintan Liu, Ciro Zanca, Federica Carbone, Edoardo Del Poggetto, Joy Gumin, Pushan Dasgupta, Sahil Seth, Sanjana Srinivasan, Frederick F. Lang, Erik P. Sulman, Philip L. Lorenzi, Lin Tan, Mengrou Shan, Zachary P. Tolstyka, Maureen Kachman, Li Zhang, Sisi Gao, Angela K. Deem, Giannicola Genovese, Pier Paolo Scaglioni, Costas A. Lyssiotis, Andrea Viale, Giulio F. Draetta
Assistant Professor, Department of Genomic Medicine
Senior Vice President, Chief Scientific Office
Professor, Departments of Genomic Medicine and Molecular & Cellular Oncology
Sewell Family Chair in Genomic Medicine in honor of Lynda Chen, M.D.