September 2019 - August 2020 Awardees (FY 2020)
June - August 2020
Pingping Hou, Ph.D. | Y. Alan Wang, Ph.D. | Ronald A. DePinho, M.D.
Cancer Discovery
Tumor Microenvironment Remodeling Enables Bypass of Oncogenic KRAS Dependency in Pancreatic Cancer
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Vivek Subbiah, M.D. | Maria Cabanillas, M.D.
The New England Journal of Medicine
Efficacy of Selpercatinib in RET-Altered Thyroid Cancers
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Pingping Hou, Ph.D., Y. Alan Wang, Ph.D. & Ronald A. DePinho, M.D.
Tumor Microenvironment Remodeling Enables Bypass of Oncogenic KRAS Dependency in Pancreatic Cancer
Oncogenic KRAS (KRAS*) is a key tumor maintenance gene in pancreatic ductal adenocarcinoma (PDAC), motivating pharmacologic targeting of KRAS* and its effectors. Here, we explored mechanisms involving the tumor microenvironment (TME) as a potential basis for resistance to targeting KRAS*. Using the inducible KrasG12D;Trp53-/- PDAC mouse model, gain-of-function screens of epigenetic regulators identified HDAC5 as the top hit enabling KRAS* independent tumor growth. HDAC5-driven escaper tumors showed a prominent neutrophil-to-macrophage switch relative to KRAS*-driven tumors. Mechanistically, HDAC5 represses Socs3, a negative regulator of chemokine CCL2, resulting in increased CCL2, which recruits CCR2+ macrophages. Correspondingly, enforced Ccl2 promotes macrophage recruitment into the TME and enables tumor recurrence following KRAS* extinction. These tumor-associated macrophages in turn provide cancer cells with trophic support including TGFβ to enable KRAS* bypass in a SMAD4-dependent manner. Our work uncovers a KRAS* resistance mechanism involving immune cell remodeling of the PDAC TME.
SIGNIFICANCE: Although KRAS* is required for PDAC tumor maintenance, tumors can recur following KRAS* extinction. The capacity of PDAC cancer cells to alter the TME myeloid cell composition to support KRAS*-independent tumor growth illuminates novel therapeutic targets that may enhance the effectiveness of therapies targeting KRAS* and its pathway components.
Pingping Hou, Avnish Kapoor, Qiang Zhang, Jiexi Li, Chang-Jiun Wu, Jun Li, Zhengdao Lan, Ming Tang, Xingdi Ma, Jeffrey J. Ackroyd, Raghu Kalluri, Jianhua Zhang, Shan Jiang, Denise J. Spring, Y. Alan Wang, and Ronald A. DePinho
Second row (left to right) : Prasenjit Dey, Peiwen Chen, Di Zhao, Andrew Chang, Denise Spring, Abhishek Dasgupta
Third row (left to right) : Jasper R. Chen, Sagar Shah, Carolyn Guan, Rumi Lee, Y. Alan Wang, Hong Seok Shim
Postdoctoral Fellow, Department of Cancer Biology
Associate Professor, Departments of Cancer Biology and Research Oversight & Integrity
Laboratory Director, DePinho Laboratory
Past President
Professor, Departments of Cancer Biology and Genomic Medical Research
Vivek Subbiah, M.D. & Maria Cabanillas, M.D.
Associate Professor, Departments of Investigational Cancer Therapeutics and Pediatrics
Chair, GMEC Curriculum Subcommittee
Clinical Medical Director, Clinical Center for Targeted Therapy
Executive Director, Cancer Medicine Research
Professor, Department of Endocrine Neoplasia and HD
Efficacy of Selpercatinib in RET-Altered Thyroid Cancers
BACKGROUND: RET mutations occur in 70% of medullary thyroid cancers, and RET fusions occur rarely in other thyroid cancers. In patients with RET-altered thyroid cancers, the efficacy and safety of selective RET inhibition are unknown.
RESULTS: In the first 55 consecutively enrolled patients with RET-mutant medullary thyroid cancer who had previously received vandetanib, cabozantinib, or both, the percentage who had a response was 69% (95% confidence interval [CI], 55 to 81), and 1-year progression-free survival was 82% (95% CI, 69 to 90). In 88 patients with RET-mutant medullary thyroid cancer who had not previously received vandetanib or cabozantinib, the percentage who had a response was 73% (95% CI, 62 to 82), and 1-year progression-free survival was 92% (95% CI, 82 to 97). In 19 patients with previously treated RET fusion–positive thyroid cancer, the percentage who had a response was 79% (95% CI, 54 to 94), and 1-year progression-free survival was 64% (95% CI, 37 to 82). The most common adverse events of grade 3 or higher were hypertension (in 21% of the patients), increased alanine aminotransferase level (in 11%), increased aspartate aminotransferase level (in 9%), hyponatremia (in 8%), and diarrhea (in 6%). Of all 531 patients treated, 12 (2%) discontinued selpercatinib owing to drug-related adverse events.
CONCLUSIONS: In this phase 1–2 trial, selpercatinib showed durable efficacy with mainly low-grade toxic effects in patients with medullary thyroid cancer with and without previous vandetanib or cabozantinib treatment. (Funded by Loxo Oncology and others; LIBRETTO-001 ClinicalTrials. gov number, NCT03157128.)
LJ Wirth, E Sherman, B Robinson, B Solomon, H Kang, J Lorch, F Worden, M Brose, J Patel, S Leboulleux, Y Godbert, F Barlesi, JC Morris, TK Owonikoko, DSW Tan, O Gautschi, J Weiss, C de la Fouchardière, ME Burkard, J Laskin, MH Taylor, M Kroiss, J Medioni, JW Goldman, TM Bauer, B Levy, VW Zhu, N Lakhani, V Moreno, K Ebata, M Nguyen, D Heirich, EY Zhu, X Huang, L Yang, J Kherani, SM Rothenberg, A Drilon, V Subbiah, MH Shah, and ME Cabanillas
March - May 2020
Michael Green, Ph.D.
Cancer Discovery
Selective Inhibition of HDAC3 Targets Synthetic Vulnerabilities and Activates Immune Surveillance in Lymphoma
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Daniel McGrail, Ph.D. | Nidhi Sahni, Ph.D. | Shiaw-Yih Lin, Ph.D.
Cancer Cell
Proteome Instability Is a Therapeutic Vulnerability in Mismatch Repair-Deficient Cancer
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Vivek Subbiah, M.D.
Cancer Discovery
Pan-Cancer Efficacy of Vemurafenib in BRAFV600-Mutant Non-Melanoma Cancers
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Xiaoguang Liu, Ph.D. | Boyi Gan, Ph.D.
Nature Cell Biology
Cystine transporter regulation of pentose phosphate pathway dependency and disulfide stress exposes a targetable metabolic vulnerability in cancer
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Pavlos Msaouel, M.D., Ph.D. | Giannicola Genovese, M.D. | Nizar Tannir, M.D., F.A.C.P.
Cancer Cell
Comprehensive Molecular Characterization Identifies Distinct Genomic and Immune Hallmarks of Renal Medullary Carcinoma
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Rashmi Krishna Murthy, M.D.
The New England Journal of Medicine
Tucatinib, Trastuzumab, and Capecitabine for HER2-Positive Metastatic Breast Cancer
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Michael Green, Ph.D.
Selective Inhibition of HDAC3 Targets Synthetic Vulnerabilities and Activates Immune Surveillance in Lymphoma
CREBBP mutations are highly recurrent in B-cell lymphomas and either inactivate its histone acetyltransferase (HAT) domain or truncate the protein. Herein, we show that these two classes of mutations yield different degrees of disruption of the epigenome, with HAT mutations being more severe and associated with inferior clinical outcome. Genes perturbed by CREBBP mutation are direct targets of the BCL6–HDAC3 onco-repressor complex. Accordingly, we show that HDAC3-selective inhibitors reverse CREBBP-mutant aberrant epigenetic programming, resulting in: (i) growth inhibition of lymphoma cells through induction of BCL6 target genes such as CDKN1A and (ii) restoration of immune surveillance due to induction of BCL6-repressed IFN pathway and antigen-presenting genes. By reactivating these genes, exposure to HDAC3 inhibitors restored the ability of tumor-infiltrating lymphocytes to kill DLBCL cells in an MHC class I and II–dependent manner, and synergized with PD-L1 blockade in a syngeneic model in vivo. Hence, HDAC3 inhibition represents a novel mechanism-based immune epigenetic therapy for CREBBP-mutant lymphomas.
SIGNIFICANCE: We have leveraged the molecular characterization of different types of CREBBP mutations to define a rational approach for targeting these mutations through selective inhibition of HDAC3. This represents an attractive therapeutic avenue for targeting synthetic vulnerabilities in CREBBP-mutant cells in tandem with promoting antitumor immunity.
Patrizia Mondello, Saber Tadros, Matt Teater, Lorena Fontan, Aaron Y. Chang, Neeraj Jain, Haopeng Yang, Shailbala Singh, Hsia-Yuan Ying, Chi-Shuen Chu, Man Chun John Ma, Eneda Toska, Stefan Alig, Matthew Durant, Elisa de Stanchina, Sreejoyee Ghosh, Anja Mottok, Loretta Nastoupil, Sattva S. Neelapu, Oliver Weigert, Giorgio Inghirami, José Baselga, Anas Younes, Cassian Yee, Ahmet Dogan, David A. Scheinberg, Robert G. Roeder, Ari M. Melnick, and Michael R. Green
Associate Professor, Departments of Lymphoma & Myeloma and Genomic Medicine
Xiaoguang Liu, Ph.D. & Boyi Gan, Ph.D.
Postdoctoral Fellow, Department of Experimental Radiation Oncology
Associate Professor, Departments of Experimental Radiation Oncology and Molecular & Cellular Oncology
Cystine transporter regulation of pentose phosphate pathway dependency and disulfide stress exposes a targetable metabolic vulnerability in cancer
SLC7A11-mediated cystine uptake is critical for maintaining redox balance and cell survival. Here we show that this comes at a significant cost for cancer cells with high levels of SLC7A11. Actively importing cystine is potentially toxic due to its low solubility, forcing cancer cells with high levels of SLC7A11 (SLC7A11high) to constitutively reduce cystine to the more soluble cysteine. This presents a significant drain on the cellular NADPH pool and renders such cells dependent on the pentose phosphate pathway. Limiting glucose supply to SLC7A11high cancer cells results in marked accumulation of intracellular cystine, redox system collapse and rapid cell death, which can be rescued by treatments that prevent disulfide accumulation. We further show that inhibitors of glucose transporters selectively kill SLC7A11high cancer cells and suppress SLC7A11high tumour growth. Our results identify a coupling between SLC7A11-associated cystine metabolism and the pentose phosphate pathway, and uncover an accompanying metabolic vulnerability for therapeutic targeting in SLC7A11high cancers.
Xiaoguang Liu, Kellen Olszewski, Yilei Zhang, Esther W. Lim, Jiejun Shi, Xiaoshan Zhang, Jie Zhang, Hyemin Lee, Pranavi Koppula, Guang Lei, Li Zhuang, M. James You, Bingliang Fang, Wei Li, Christian M. Metallo, Masha V. Poyurovsky, and Boyi Gan
Daniel McGrail, Ph.D., Nidhi Sahni, Ph.D. & Shiaw-Yih Lin, Ph.D.
Proteome Instability Is a Therapeutic Vulnerability in Mismatch Repair-Deficient Cancer
Deficient DNA mismatch repair (dMMR) induces a hypermutator phenotype that can lead to tumorigenesis; however, the functional impact of the high mutation burden resulting from this phenotype remains poorly explored. Here, we demonstrate that dMMR-induced destabilizing mutations lead to proteome instability in dMMR tumors, resulting in an abundance of misfolded protein aggregates. To compensate, dMMR cells utilize a Nedd8-mediated degradation pathway to facilitate clearance of misfolded proteins. Blockade of this Nedd8 clearance pathway with MLN4924 causes accumulation of misfolded protein aggregates, ultimately inducing immunogenic cell death in dMMR cancer cells. To leverage this immunogenic cell death, we combined MLN4924 treatment with PD1 inhibition and found the combination was synergistic, significantly improving efficacy over either treatment alone.
Daniel J. McGrail, Jeannine Garnett, Jun Yin, Hui Dai, David J.H. Shih, Truong Nguyen Anh Lam, Yang Li, Chaoyang Sun, Yongsheng Li, Rosemarie Schmandt, Ji Yuan Wu, Limei Hu, Yulong Liang, Guang Peng, Eric Jonasch, David Menter, Melinda S. Yates, Scott Kopetz, Karen H. Lu, Russell Broaddus, Gordon B. Mills, Nidhi Sahni, and Shiaw-Yih Lin
Postdoctoral Fellow, Department of Systems Biology
Assistant Professor, Departments of Epigenetics & Molecular Carcinogenesis and Bioinformatics & Computational Biology
Professor and Deputy Chair, Department of Systems Biology
Pavlos Msaouel, M.D., Ph.D., Giannicola Genovese, M.D. & Nizar Tannir, M.D., F.A.C.P.
Assistant Professor, Departments of Genitourinary Medical Oncology and Translational Molecular Pathology
Assistant Professor, Departments of Genitourinary Medical Oncology and Genomic Medical Research
Professor, Department of Genitourinary Medical Oncology
Comprehensive Molecular Characterization Identifies Distinct Genomic and Immune Hallmarks of Renal Medullary Carcinoma
Renal medullary carcinoma (RMC) is a highly lethal malignancy that mainly afflicts young individuals of African descent and is resistant to all targeted agents used to treat other renal cell carcinomas. Comprehensive genomic and transcriptomic profiling of untreated primary RMC tissues was performed to elucidate the molecular landscape of these tumors. We found that RMC was characterized by high replication stress and an abundance of focal copy-number alterations associated with activation of the stimulator of the cyclic GMP-AMP synthase interferon genes (cGAS-STING) innate immune pathway. Replication stress conferred a therapeutic vulnerability to drugs targeting DNA-damage repair pathways. Elucidation of these previously unknown RMC hallmarks paves the way to new clinical trials for this rare but highly lethal malignancy
P Msaouel, GG Malouf, X Su, H Yao, DN Tripathi, M Soeung, J Gao, P Rao, C Coarfa, CJ Creighton, JP Bertocchio, S Kunnimalaiyaan, AS Multani, J Blando, R He, DD Shapiro, L Perelli, S Srinivasan, F Carbone, PG Pilié, M Karki, RNH Seervai, BH Vokshi, D Lopez-Terrada, EH Cheng, X Tang, W Lu, II Wistuba, TC Thompson, I Davidson, V Giuliani, K Schlacher, A Carugo, TP Heffernan, P Sharma, JA Karam, CG Wood, CL Walker, G Genovese, and NM Tannir
Vivek Subbiah, M.D.
Pan-Cancer Efficacy of Vemurafenib in BRAFV600-Mutant Non-Melanoma Cancers
BRAFV600 mutations occur in a wide range of tumor types, and RAF inhibition has become standard in several of these cancers. Despite this progress, BRAFV600 mutations have historically been considered a clear demonstration of tumor lineage context–dependent oncogene addiction, based predominantly on the insensitivity to RAF inhibition in colorectal cancer. However, the true broader activity of RAF inhibition pan-cancer remains incompletely understood. To address this, we conducted a multicohort “basket” study of the BRAF inhibitor vemurafenib in non-melanoma BRAFV600 mutation–positive solid tumors. In total, 172 patients with 26 unique cancer types were treated, achieving an overall response rate of 33% and median duration of response of 13 months. Responses were observed in 13 unique cancer types, including historically treatment-refractory tumor types such as cholangiocarcinoma, sarcoma, glioma, neuroendocrine carcinoma, and salivary gland carcinomas. Collectively, these data demonstrate that single-agent BRAF inhibition has broader clinical activity than previously recognized.
SIGNIFICANCE: These data suggest that BRAFV600 mutations lead to oncogene addiction and are clinically actionable in a broad range of non-melanoma cancers, including tumor types in which RAF inhibition is not currently considered standard of care.
Vivek Subbiah, Igor Puzanov, Jean-Yves Blay, Ian Chau, A. Craig Lockhart, Noopur S. Raje, Juergen Wolf, José Baselga, Funda Meric-Bernstam, Jason Roszik, Eli L. Diamond, Gregory J. Riely, Eric J. Sherman, Todd Riehl, Bethany Pitcher, and David M. Hyman
Associate Professor, Departments of Investigational Cancer Therapeutics and Pediatrics
Chair, GMEC Curriculum Subcommittee
Clinical Medical Director, Clinical Center for Targeted Therapy
Executive Director, Cancer Medicine Research
Rashmi Krishna Murthy, M.D.
Associate Professor, Department of Breast Medical Oncology
Tucatinib, Trastuzumab, and Capecitabine for HER2-Positive Metastatic Breast Cancer
BACKGROUND: Patients with human epidermal growth factor receptor 2 (HER2)–positive metastatic breast cancer who have disease progression after therapy with multiple HER2-targeted agents have limited treatment options. Tucatinib is an investigational, oral, highly selective inhibitor of the HER2 tyrosine kinase.
RESULTS: Progression-free survival at 1 year was 33.1% in the tucatinib-combination group and 12.3% in the placebo-combination group (hazard ratio for disease progression or death, 0.54; 95% confidence interval [CI], 0.42 to 0.71; P<0.001), and the median duration of progression- free survival was 7.8 months and 5.6 months, respectively. Overall survival at 2 years was 44.9% in the tucatinib-combination group and 26.6% in the placebo-combination group (hazard ratio for death, 0.66; 95% CI, 0.50 to 0.88; P=0.005), and the median overall survival was 21.9 months and 17.4 months, respectively. Among the patients with brain metastases, progression-free survival at 1 year was 24.9% in the tucatinib-combination group and 0% in the placebo-combination group (hazard ratio, 0.48; 95% CI, 0.34 to 0.69; P<0.001), and the median progression- free survival was 7.6 months and 5.4 months, respectively. Common adverse events in the tucatinib group included diarrhea, palmar–plantar erythrodysesthesia syndrome, nausea, fatigue, and vomiting. Diarrhea and elevated aminotransferase levels of grade 3 or higher were more common in the tucatinib-combination group than in the placebo-combination group.
CONCLUSIONS: In heavily pretreated patients with HER2-positive metastatic breast cancer, including those with brain metastases, adding tucatinib to trastuzumab and capecitabine resulted in better progression-free survival and overall survival outcomes than adding placebo; the risks of diarrhea and elevated aminotransferase levels were higher with tucatinib. (Funded by Seattle Genetics; HER2CLIMB ClinicalTrials. gov number, NCT02614794.)
R.K. Murthy, S. Loi, A. Okines, E. Paplomata, E. Hamilton, S.A. Hurvitz, N.U. Lin, V. Borges, V. Abramson, C. Anders, P.L. Bedard, M. Oliveira, E. Jakobsen, T. Bachelot, S.S. Shachar, V. Müller, S. Braga, F.P. Duhoux, R. Greil, D. Cameron, L.A. Carey, G. Curigliano, K. Gelmon, G. Hortobagyi, I. Krop, S. Loibl, M. Pegram, D. Slamon, M.C. Palanca‑Wessels, L. Walker, W. Feng, and E.P. Winer
December 2019 - February 2020
Moran Amit, M.D., Ph.D. | George A. Calin, M.D., Ph.D. | Jeffrey N. Myers, M.D., Ph.D.
Nature
Loss of p53 drives neuron reprogramming in head and neck cancer
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Sangeeta Goswami, M.D., Ph.D. | Padmanee Sharma, M.D., Ph.D.
Nature Medicine
Immune profiling of human tumors identifies CD73 as a combinatorial target in glioblastoma
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David Marin, M.D. | Katy Rezvani, M.D., Ph.D.
The New England Journal of Medicine
Use of CAR-Transduced Natural Killer Cells in CD19-Positive Lymphoid Tumors
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Jianjun Gao, M.D., Ph.D. | Rafet Basar, M.D., Ph.D. | Jennifer A. Wargo, M.D. M.M.Sc
Nature
B cells and tertiary lymphoid structures promote immunotherapy response
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Karen Hoffman, M.D., M.H.Sc., M.P.H.
Journal of the American Medical Association
Patient-Reported Outcomes Through 5 Years for Active Surveillance, Surgery, Brachytherapy, or External Beam Radiation With or Without Androgen Deprivation Therapy for Localized Prostate Cancer
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Hussein Tawbi, M.D.
Nature
B cells are associated with survival and immunotherapy response in sarcoma
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Moran Amit, M.D., Ph.D., George A. Calin, M.D., Ph.D. & Jeffrey N. Myers, M.D., Ph.D.
Loss of p53 drives
neuron reprogramming in head and neck cancer
The solid tumour microenvironment includes nerve fibres that arise from the peripheral nervous system. Recent work indicates that newly formed adrenergic nerve fibres promote tumour growth, but the origin of these nerves and the mechanism of their inception are unknown. Here, by comparing the transcriptomes of cancer-associated trigeminal sensory neurons with those of endogenous neurons in mouse models of oral cancer, we identified an adrenergic differentiation signature. We show that loss of TP53 leads to adrenergic transdifferentiation of tumour-associated sensory nerves through loss of the microRNA miR- 34a. Tumour growth was inhibited by sensory denervation or pharmacological blockade of adrenergic receptors, but not by chemical sympathectomy of pre-existing adrenergic nerves. A retrospective analysis of samples from oral cancer revealed that p53 status was associated with nerve density, which was in turn associated with poor clinical outcomes. This crosstalk between cancer cells and neurons represents mechanism by which tumour-associated neurons are reprogrammed towards an adrenergic phenotype that can stimulate tumour progression, and is a potential target for anticancer therapy.
Moran Amit, Hideaki Takahashi, Mihnea Paul Dragomir, Antje Lindemann, Frederico O. Gleber-Netto, Curtis R. Pickering, Simone Anfossi, Abdullah A. Osman, Yu Cai, Rong Wang, Erik Knutsen, Masayoshi Shimizu, Cristina Ivan, Xiayu Rao, Jing Wang, Deborah A. Silverman, Samantha Tam, Mei Zhao, Carlos Caulin, Assaf Zinger, Ennio Tasciotti, Patrick M. Dougherty, Adel El-Naggar, George A. Calin, and Jeffrey N. Myers
Assistant Professor, Department of Head & Neck Surgery
Professor, Departments of Translation Molecular Pathology and Leukemia
Felix L. Hass Professorship in Basic Science
Chair, Department of Head & Neck Surgery
A.J. Ballantyne Distinguished Chair
Jianjun Gao, M.D., Ph.D., Rafet Basar, M.D., Ph.D. & Jennifer A. Wargo, M.D. M.M.Sc
Associate Professor, Department of Genitourinary Medical Oncology
Assistant Professor, Department of Stem Cell Transplantation
R. Lee Clark Professor of Surgical Oncology and Genomic Medicine
B cells and tertiary lymphoid structures promote immunotherapy response
Treatment with immune checkpoint blockade (ICB) has revolutionized cancer therapy. Until now, predictive biomarkers and strategies to augment clinical response have largely focused on the T cell compartment. However, other immune subsets may also contribute to anti-tumour immunity, although these have been less well-studied in ICB treatment. A previously conducted neoadjuvant ICB trial in patients with melanoma showed via targeted expression profiling that B cell signatures were enriched in the tumours of patients who respond to treatment versus non-responding patients. To build on this, here we performed bulk RNA sequencing and found that B cell markers were the most differentially expressed genes in the tumours of responders versus non-responders. Our findings were corroborated using a computational method (MCP-counter) to estimate the immune and stromal composition in this and two other ICB-treated cohorts (patients with melanoma and renal cell carcinoma). Histological evaluation highlighted the localization of B cells within tertiary lymphoid structures. We assessed the potential functional contributions of B cells via bulk and single-cell RNA sequencing, which demonstrate clonal expansion and unique functional states of B cells in responders. Mass cytometry showed that switched memory B cells were enriched in the tumours of responders. Together, these data provide insights into the potential role of B cells and tertiary lymphoid structures in the response to ICB treatment, with implications for the development of biomarkers and therapeutic targets.
BA Helmink, SM Reddy, J Gao, S Zhang, R Basar, R Thakur, K Yizhak, M Sade-Feldman, J Blando, G Han, V Gopalakrishnan, Y Xi, H Zhao, RN Amaria, HA Tawbi, AP Cogdil, W Liu, VS LeBleu, FG Kugeratski, S Patel, MA Davies, P Hwu, JE Lee, JE Gershenwald, A Lucci, R Arora, S Woodman, E Keung, PO Gaudreau, A Reuben, CN Spencer, EM Burton, LE Haydu, AJ Lazar, R Zapassodi, CW Hudgens, DA Ledesma, S Ong, M Bailey, S Warren, D Rao, O Krijgsman, EA Rozeman, D Peeper, CU Blank, TN Schumacher, LH Butterfield, MA Zelazowska, KM McBride, R Kalluri, J Allison, F Petitprez, W Herman Fridman, C Sautès-Fridman, N Hacohen, K Rezvani, P Sharma, MT Tetzlaff, L Wang, and JA Wargo
Sangeeta Goswami, M.D., Ph.D. & Padmanee Sharma, M.D., Ph.D.
Immune profiling of human tumors identifies CD73 as a combinatorial target in glioblastoma
Immune checkpoint therapy with anti- CTLA-4 and anti-PD-1/PD-L1 has revolutionized the treatment of many solid tumors. However, the clinical efficacy of immune checkpoint therapy is limited to a subset of patients with specific tumor types. Multiple clinical trials with combinatorial immune checkpoint strategies are ongoing; however, the mechanistic rationale for tumor-specific targeting of immune checkpoints is elusive. To garner an insight into tumor-specific immunomodulatory targets, we analyzed 94 patients representing five different cancer types, including those that respond relatively well to immune checkpoint therapy and those that do not, such as glioblastoma multiforme, prostate cancer and colorectal cancer. Through mass cytometry and single-cell RNA sequencing, we identified a unique population of CD73hi macrophages in glioblastoma multiforme that persists after anti-PD-1 treatment. To test if targeting CD73 would be important for a successful combination strategy in glioblastoma multiforme, we performed reverse translational studies using CD73-/- mice. We found that the absence of CD73 improved survival in a murine model of glioblastoma multiforme treated with anti-CTLA-4 and anti-PD-1. Our data identified CD73 as a specific immunotherapeutic target to improve antitumor immune responses to immune checkpoint therapy in glioblastoma multiforme and demonstrate that comprehensive human and reverse translational studies can be used for rational design of combinatorial immune checkpoint strategies.
Sangeeta Goswami, Thomas Walle, Andrew E. Cornish, Sreyashi Basu, Swetha Anandhan, Irina Fernandez, Luis Vence, Jorge Blando, Hao Zhao, Shalini Singh Yadav, Martina Ott, Ling Y. Kong, Amy B. Heimberger, John de Groot, Boris Sepesi, Michael Overman, Scott Kopetz, James P. Allison, Dana Pe’er, and Padmanee Sharma
Middle Row : Sreyashi Basu, Swetha Anandhan, Dr. Scott Kopetz
Bottom Row : Shalini Singh, Dr. Jim Allison
Assistant Professor, Departments of Genitourinary Medical Oncology and Immunology
Professor, Departments of Genitourinary Medical Oncology & Immunology
Co-Director, Parker Institute for Cancer Immunotherapy at MD Anderson
Scientific Director, Immunotherapy Platform (IMT)
T.C. and Jeanette Hsu Endowed Chair in Cell Biology
Karen Hoffman, M.D., M.H.Sc., M.P.H.
Associate Professor, Department of Radiation Oncology
Patient-Reported Outcomes Through 5 Years for Active Surveillance, Surgery, Brachytherapy, or External Beam Radiation With or Without Androgen Deprivation Therapy for Localized Prostate Cancer
IMPORTANCE: Understanding adverse effects of contemporary treatment approaches for men with favorable-risk and unfavorable-risk localized prostate cancer could inform treatment selection.
RESULTS: A total of 2005 men met inclusion criteria and completed the baseline and at least 1 postbaseline survey (median [interquartile range] age, 64 [59-70] years; 1529 of 1993 participants [77%] were non-Hispanic white). For men with favorable-risk prostate cancer, nerve-sparing prostatectomy was associated with worse urinary incontinence at 5 years (adjusted mean difference, -10.9 [95% CI, -14.2 to -7.6]) and sexual function at 3 years (adjusted mean difference, -15.2 [95% CI, -18.8 to -11.5]) compared with active surveillance. Low-dose-rate brachytherapy was associated with worse urinary irritative (adjusted mean difference, -7.0 [95% CI, -10.1 to -3.9]), sexual (adjusted mean difference, -10.1 [95% CI, -14.6 to -5.7]), and bowel (adjusted mean difference, -5.0 [95% CI, -7.6 to -2.4]) function at 1 year compared with active surveillance. EBRT was associated with urinary, sexual, and bowel function changes not clinically different from active surveillance at any time point through 5 years. For men with unfavorable-risk disease, EBRT with ADT was associated with lower hormonal function at 6 months (adjusted mean difference, -5.3 [95% CI, -8.2 to -2.4]) and bowel function at 1 year (adjusted mean difference, -4.1 [95% CI, -6.3 to -1.9]), but better sexual function at 5 years (adjusted mean difference, 12.5 [95% CI, 6.2-18.7]) and incontinence at each time point through 5 years (adjusted mean difference, 23.2 [95% CI, 17.7- 28.7]), than prostatectomy.
CONCLUSIONS AND RELEVANCE: In this cohort of men with localized prostate cancer, most functional differences associated with contemporary management options attenuated by 5 years. However, men undergoing prostatectomy reported clinically meaningful worse incontinence through 5 years compared with all other options, and men undergoing prostatectomy for unfavorable-risk disease reported worse sexual function at 5 years compared
Karen E. Hoffman, David F. Penson, Zhiguo Zhao, Li-Ching Huang, Ralph Conwill, Aaron A. Laviana, Daniel D. Joyce, Amy N. Luckenbaugh, Michael Goodman, Ann S. Hamilton, Xiao-Cheng Wu, Lisa E. Paddock, Antoinette Stroup, Matthew R. Cooperberg, Mia Hashibe, Brock B. O’Neil, Sherrie H. Kaplan, Sheldon Greenfield, Tatsuki Koyama, Daniel A. Barocas
David Marin, M.D., & Katy Rezvani, M.D., Ph.D.
Use of CAR-Transduced Natural Killer Cells in CD19-Positive Lymphoid Tumors
BACKGROUND: Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy has shown remarkable clinical efficacy in B-cell cancers. However, CAR T cells can induce substantial toxic effects, and the manufacture of the cells is complex. Natural killer (NK) cells that have been modified to express an anti-CD19 CAR have the potential to overcome these limitations.
METHODS: In this phase 1 and 2 trial, we administered HLA-mismatched anti-CD19 CAR-NK cells derived from cord blood to 11 patients with relapsed or refractory CD19-positive cancers (non-Hodgkin’s lymphoma or chronic lymphocytic leukemia [CLL]). NK cells were transduced with a retroviral vector expressing genes that encode anti-CD19 CAR, interleukin-15, and inducible caspase 9 as a safety switch. The cells were expanded ex vivo and administered in a single infusion at one of three doses (1×105, 1×106, or 1×107 CAR-NK cells per kilogram of body weight) after lymphodepleting chemotherapy.
RESULTS: The administration of CAR-NK cells was not associated with the development of cytokine release syndrome, neurotoxicity, or graft-versus- host disease, and there was no increase in the levels of inflammatory cytokines, including interleukin-6, over baseline. The maximum tolerated dose was not reached. Of the 11 patients who were treated, 8 (73%) had a response; of these patients, 7 (4 with lymphoma and 3 with CLL) had a complete remission, and 1 had remission of the Richter’s transformation component but had persistent CLL. Responses were rapid and seen within 30 days after infusion at all dose levels. The infused CAR-NK cells expanded and persisted at low levels for at least 12 months.
CONCLUSIONS: Among 11 patients with relapsed or refractory CD19-positive cancers, a majority had a response to treatment with CAR-NK cells without the development of major toxic effects. (Funded by the M.D. Anderson Cancer Center CLL and Lymphoma Moonshot and the National Institutes of Health; ClinicalTrials.gov number, NCT03056339.)
Enli Liu, David Marin, Pinaki Banerjee, Homer A. Macapinlac, Philip Thompson, Rafet Basar, Lucila Nassif Kerbauy, Bethany Overman, Peter Thall, Mecit Kaplan, Vandana Nandivada, Indresh Kaur, Ana Nunez Cortes, Kai Cao, May Daher, Chitra Hosing, Evan N. Cohen, Partow Kebriaei, Rohtesh Mehta, Sattva Neelapu, Yago Nieto, Michael Wang, William Wierda, Michael Keating, Richard Champlin, Elizabeth J. Shpall, and Katayoun Rezvani
Second row (L-R) : Mecit Kaplan MS, Homer Macapinlac M.D., Peter Thall Ph.D., Partow Kebriaei M.D., Lucila Nassif Kerbauy M.D.
Third row (L-R) : Evan Cohen Ph.D., May Daher M.D., Kai Cao Ph.D., Sattva Neelapu M.D., Ana Nunez Cortes M.D.
Fourth row (L-R) : Rohtesh Mehta M.D., Pinaki Banerjee Ph.D., Vandana Nandivada M.D., Yago Nieto M.D., Richard Champlin M.D.
Professor, Department of Stem Cell Transplantation
Professor, Department of Stem Cell Transplantation
Director, Cellular Therapy
Director, Translation Research
Medical Director, GMP Cell Therapy
Hussein Tawbi, M.D.
Professor, Department of Melanoma Medical Oncology and Investigational Cancer Therapeutics
Deputy Chair, Department of Melanoma Medical Oncology
Director of Melanoma Clinical Research & Early Drug Development
Co-Director, MD Anderson Brain Metastasis Clinic
B cells are associated with survival and immunotherapy response in sarcoma
Soft-tissue sarcomas represent a heterogeneous group of cancer, with more than 50 histological subtypes. The clinical presentation of patients with different subtypes is often atypical, and responses to therapies such as immune checkpoint blockade vary widely. To explain this clinical variability, here we study gene expression profiles in 608 tumours across subtypes of soft-tissue sarcoma. We establish an immune-based classification on the basis of the composition of the tumour microenvironment and identify five distinct phenotypes: immune-low (A and B), immune-high (D and E), and highly vascularized (C) groups. In situ analysis of an independent validation cohort shows that class E was characterized by the presence of tertiary lymphoid structures that contain T cells and follicular dendritic cells and are particularly rich in B cells. B cells are the strongest prognostic factor even in the context of high or low CD8+ T cells and cytotoxic contents. The class-E group demonstrated improved survival and a high response rate to PD1 blockade with pembrolizumab in a phase 2 clinical trial. Together, this work confirms the immune subtypes in patients with soft-tissue sarcoma, and unravels the potential of B-cell-rich tertiary lymphoid structures to guide clinical decision-making and treatments, which could have broader applications in other diseases.
Florent Petitprez, Aurélien de Reyniès, Emily Z. Keung, Tom Wei-Wu Chen, Cheng-Ming Sun, Julien Calderaro, Yung-Ming Jeng, Li-Ping Hsiao, Laetitia Lacroix, Antoine Bougoüin, Marco Moreira, Guillaume Lacroix, Ivo Natario, Julien Adam, Carlo Lucchesi, Yec’han Laizet, Maud Toulmonde, Melissa A. Burgess, Vanessa Bolejack, Denise Reinke, Khalid M. Wani, Wei-Lien Wang, Alexander J. Lazar, Christina L. Roland, Jennifer A. Wargo, Antoine Italiano, Catherine Sautès-Fridman, Hussein A. Tawbi, and Wolf H. Fridman
• September - November 2019
Scott Kopetz, M.D., Ph.D.
The New England Journal of Medicine
Encorafenib, Binimetinib, and Cetuximab in BRAF V600E–Mutated Colorectal Cancer
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Padmanee Sharma, M.D., Ph.D.
Cell
Differences in Tumor Microenvironment Dictate T Helper Lineage Polarization and Response to Immune Checkpoint Therapy
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Jacqulyne Ponville Robichaux, Ph.D. | John Victor Heymach, M.D., Ph.D.
Cancer Cell
Pan-Cancer Landscape and Analysis of ERBB2 Mutations Identifies Poziotinib as a Clinically Active Inhibitor and Enhancer of T-DM1 Activity
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Scott Kopetz, M.D., Ph.D.
Encorafenib, Binimetinib, and Cetuximab in BRAF V600E–Mutated Colorectal Cancer
BACKGROUND: Patients with metastatic colorectal cancer with the BRAF V600E mutation have a poor prognosis, with a median overall survival of 4 to 6 months after failure of initial therapy. Inhibition of BRAF alone has limited activity because of pathway reactivation through epidermal growth factor receptor signaling.
RESULTS: The median overall survival was 9.0 months in the triplet-therapy group and 5.4 months in the control group (hazard ratio for death, 0.52; 95% confidence interval [CI], 0.39 to 0.70; P<0.001). The confirmed response rate was 26% (95% CI, 18 to 35) in the triplet-therapy group and 2% (95% CI, 0 to 7) in the control group (P<0.001). The median overall survival in the doublet-therapy group was 8.4 months (hazard ratio for death vs. control, 0.60; 95% CI, 0.45 to 0.79; P<0.001). Adverse events of grade 3 or higher occurred in 58% of patients in the triplet-therapy group, in 50% in the doublet-therapy group, and in 61% in the control group.
CONCLUSIONS: A combination of encorafenib, cetuximab, and binimetinib resulted in significantly longer overall survival and a higher response rate than standard therapy in patients with metastatic colorectal cancer with the BRAF V600E mutation. (Funded by Array BioPharma and others; BEACON CRC ClinicalTrials.gov number, NCT02928224; EudraCT number, 2015- 005805-35.)
S Kopetz, A Grothey, R Yaeger, E Van Cutsem, J Desai, T Yoshino, H Wasan, F Ciardiello, F Loupakis, YS Hong, N Steeghs, TK Guren, HT Arkenau, P Garcia‑Alfonso, P Pfeiffer, S Orlov, S Lonardi, E Elez, TW Kim, JHM Schellens, C Guo, A Krishnan, J Dekervel, V Morris, A Calvo Ferrandiz, LS Tarpgaard, M Braun, A Gollerkeri, C Keir, K Maharry, M Pickard, J Christy‑Bittel, L Anderson, V Sandor and J Tabernero
Professor, Department of GI Medical Oncology
Middle Row (L-R ): Tracy Trevino and Jamie Farber
Bottom Row: Alex Sorokin
Jacqulyne Robichaux, Ph.D. & John Heymach, M.D., Ph.D.
Assistant Professor, Department of Thoracic Head & Neck Medical Oncology
Professor, Departments of Thoracic Head & Neck Medical Oncology and Cancer Biology
Chair, Department of Thoracic Head & Neck Medical Oncology
Pan-Cancer Landscape and Analysis of ERBB2 Mutations Identifies Poziotinib as a Clinically Active Inhibitor and Enhancer of T-DM1 Activity
We characterized the landscape and drug sensitivity of ERBB2 (HER2) mutations in cancers. In 11 datasets (n = 211,726), ERBB2 mutational hotspots varied across 25 tumor types. Common HER2 mutants yielded differential sensitivities to eleven EGFR/HER2 tyrosine kinase inhibitors (TKIs) in vitro, and molecular dynamics simulations revealed that mutants with a reduced drug-binding pocket volume were associated with decreased affinity for larger TKIs. Overall, poziotinib was the most potent HER2 mutant-selective TKI tested. Phase II clinical testing in ERBB2 exon 20-mutant non-small cell lung cancer resulted in a confirmed objective response rate of 42% in the first 12 evaluable patients. In pre-clinical models, poziotinib upregulated HER2 cell-surface expression and potentiated the activity of T-DM1, resulting in complete tumor regression with combination treatment.
Jacqulyne P. Robichaux, Yasir Y. Elamin, R.S.K. Vijayan, Monique B. Nilsson, Lemei Hu, Junqin He, Fahao Zhang, Marlese Pisegna, Alissa Poteete, Huiying Sun, Shuai Li, Ting Chen, Han Han, Marcelo Vailati Negrao, Jordi Rodon Ahnert, Lixia Diao, Jing Wang, Xiuning Le, Funda Meric-Bernstam, Mark Routbort, Brent Roeck, Zane Yang, Victoria M. Raymond, Richard B. Lanman, Garrett M. Frampton, Vincent A. Miller, Alexa B.Schrock, Lee A. Albacker, Kwok-kin Wong, Jason B. Cross and John V. Heymach
Middle (L-R ): Yasir Elamin & Xiuning Le
Back (L-R ): Monique Nilsson & Jacqulyne Robichaux
Not pictured : Jason Cross
Padmanee Sharma, M.D., Ph.D.
Differences in Tumor Microenvironment Dictate T Helper Lineage Polarization and Response to Immune Checkpoint Therapy
Immune checkpoint therapy (ICT) shows encouraging results in a subset of patients with metastatic castration-resistant prostate cancer (mCRPC) but still elicits a sub-optimal response among those with bone metastases. Analysis of patients’ bone marrow samples revealed increased Th17 instead of Th1 subsets after ICT. To further evaluate the different tumor microenvironments, we injected mice with prostate tumor cells either subcutaneously or intraosseously. ICT in the subcutaneous CRPC model significantly increases intra-tumoral Th1 subsets and improves survival. However, ICT fails to elicit an anti- tumor response in the bone CRPC model despite an increase in the intra-tumoral CD4 T cells, which are polarized to Th17 rather than Th1 lineage. Mechanistically, tumors in the bone promote osteoclast- mediated bone resorption that releases TGF-β, which restrains Th1 lineage development. Blocking TGF-β along with ICT increases Th1 subsets and promotes clonal expansion of CD8 T cells and subsequent regression of bone CRPC and improves survival.
Shiping Jiao, Sumit K. Subudhi, Ana Aparicio, Zhongqi Ge, Baoxiang Guan, Yuji Miura and Padmanee Sharma
Professor, Departments of Genitourinary Medical Oncology & Immunology
Co-Director, Parker Institute for Cancer Immunotherapy at MD Anderson
Scientific Director, Immunotherapy Platform (IMT)