September 2018 - August 2019 Awardees (FY 2019)
• June - August 2019
Li-Chuan Chan, Ph.D. | Liuqing Yang, Ph.D.
Nature Immunology
Oncogenic lncRNA downregulates cancer cell antigen presentation and intrinsic tumor suppression
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Filippo G. Giancotti, M.D., Ph.D.
Cancer Cell
The Polycomb Repressor Complex 1 Drives Double-Negative Prostate Cancer Metastasis by Coordinating Stemness and Immune Suppression
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Florencia McAllister, M.D.
Cell
Tumor Microbiome Diversity and Composition Influence Pancreatic Cancer Outcomes
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Peiwen Chen, Ph.D. | Y. Alan Wang, Ph.D. | Ronald A. DePinho, M.D.
Cancer Cell
Symbiotic Macrophage-Glioma Cell Interactions Reveal Synthetic Lethality in PTEN-Null Glioma
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Nitin Jain, M.B.B.S. | Varsha Gandhi, Ph.D. | William Wierda, M.D., Ph.D.
The New England Journal of Medicine
Ibrutinib and Venetoclax for First-Line Treatment of CLL
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Xiaofei Zhou, Ph.D. | Shao-Cong Sun, Ph.D.
Nature Immunology
The deubiquitinase Otub1 controls the activation of CD8+ T cells and NK cells by regulating IL-15-mediated priming
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Li-Chuan Chan, Ph.D. & Liuqing Yang, Ph.D.
Oncogenic lncRNA downregulates cancer cell antigen presentation and intrinsic tumor suppression
How tumor cells genetically lose antigenicity and evade immune checkpoints remains largely elusive. We report that tissuespecific expression of the human long noncoding RNA LINK-A in mouse mammary glands initiates metastatic mammary gland tumors, which phenotypically resemble human triple-negative breast cancer (TNBC). LINK-A expression facilitated crosstalk between phosphatidylinositol-(3,4,5)-triphosphate and inhibitory G-protein-coupled receptor (GPCR) pathways, attenuating protein kinase A-mediated phosphorylation of the E3 ubiquitin ligase TRIM71. Consequently, LINK-A expression enhanced K48-polyubiquitination- mediated degradation of the antigen peptide-loading complex (PLC) and intrinsic tumor suppressors Rb and p53. Treatment with LINK-A locked nucleic acids or GPCR antagonists stabilized the PLC components, Rb and p53, and sensitized mammary gland tumors to immune checkpoint blockers. Patients with programmed ccll death protein1(PD-1) blockade-resistant TNBC exhibited elevated LINK-A levels and downregulated PLC components. Hence we demonstrate lncRNA-dependent downregulation of antigenicity and intrinsic tumor suppression, which provides the basis for developing combinational immunotherapy treatment regimens and early TNBC prevention.
Qingsong Hu, Youqiong Ye, Li-Chuan Chan , Yajuan Li, Ke Liang, Aifu Lin, Sergey D. Egranov, Yaohua Zhang, Weiya Xia, Jing Gong, Yinghong Pan, Sujash S. Chatterjee, Jun Yao , Kurt W. Evans, Tina K. Nguyen, Peter K. Park, Jiewei Liu, Cristian Coarfa, Sri Ramya Donepudi, Vasanta Putluri, Nagireddy Putluri, Arun Sreekumar, Chandrashekar R. Ambati, David H. Hawke, Jeffrey R. Marks, Preethi H. Gunaratne, Abigail S. Caudle , Aysegul A. Sahin , Gabriel N. Hortobagyi , Funda Meric-Bernstam , Lieping Chen, Dihua Yu , Mien-Chie Hung, Michael A. Curran , Leng Han, Chunru Lin and Liuqing Yang
Postdoctoral Fellow, Molecular & Cellular Oncology
Associate Professor, Department of Molecular & Cellular Oncology
Peiwen Chen, Ph.D., Y. Alan Wang, Ph.D. & Ronald A. DePinho, M.D.
Postdoctoral Fellow, Cancer Biology
Associate Professor, Department of Cancer Biology
Laboratory Director, DePinho Laboratory
Past President
Professor, Department of Cancer Biology
Harry Graves Burkhart III in Cancer Research, Chair
Symbiotic Macrophage-Glioma Cell Interactions Reveal Synthetic Lethality in PTEN-Null Glioma
Heterotypic interactions across diverse cell types can enable tumor progression and hold the potential to expand therapeutic interventions. Here, combined profiling and functional studies of glioma cells in glioblastoma multiforme (GBM) models establish that PTEN deficiency activates YAP1, which directly upregulates lysyl oxidase (LOX) expression. Mechanistically, secreted LOX functions as a potent macrophage chemoattractant via activation of the β1 integrin-PYK2 pathway in macrophages. These infiltrating macrophages secrete SPP1, which sustains glioma cell survival and stimulates angiogenesis. In PTEN -null GBM models, LOX inhibition markedly suppresses macrophage infiltration and tumor progression. Correspondingly, YAP1-LOX and β1 integrin-SPP1 signaling correlates positively with higher macrophage density and lower overall survival in GBM patients. This symbiotic glioma-macrophage interplay provides therapeutic targets specifically for PTEN -deficient GBM.
Peiwen Chen, Di Zhao, Jun Li, Xin Liang, Jiexi Li, Andrew Chang, Verlene K. Henry, Zhengdao Lan, Denise J. Spring, Ganesh Rao, 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
Filippo G. Giancotti, M.D., Ph.D.
The Polycomb Repressor Complex 1 Drives Double-Negative Prostate Cancer Metastasis by Coordinating Stemness and Immune Suppression
The mechanisms that enable immune evasion at metastatic sites are poorly understood. We show that the Polycomb Repressor Complex 1 (PRC1) drives colonization of the bones and visceral organs in double-negative prostate cancer (DNPC). In vivo genetic screening identifies CCL2 as the top prometastatic gene induced by PRC1. CCL2 governs self-renewal and induces the recruitment of M2-like tumor- associated macrophages and regulatory T cells, thus coordinating metastasis initiation with immune suppression and neoangiogenesis. A catalytic inhibitor of PRC1 cooperates with immune checkpoint therapy to reverse these processes and suppress metastasis in genetically engineered mouse transplantation models of DNPC. These results reveal that PRC1 coordinates stemness with immune evasion and neoangiogenesis and point to the potential clinical utility of targeting PRC1 in DNPC.
Wenjing Su, Hyun Ho Han, Yan Wang, Boyu Zhang, Bing Zhou, Yuanming Cheng, Alekya Rumandla, Sreeharsha Gurrapu, Goutam Chakraborty, Jie Su, Guangli Yang, Xin Liang, Guocan Wang, Neal Rosen, Howard I. Scher, Ouathek Ouerfelli and Filippo G. Giancotti
Professor, Cancer Biology
Olla S. Stribling Distinguished Chair in Cancer Research
Scientific Director, David H. Koch Center for Applied Research of GU Cancers
Co-Leader, Prostate Cancer Moon Shot Program
Nitin Jain, M.B.B.S., Varsha Gandhi, Ph.D. & William Wierda, M.D., Ph.D.
Associate Professor, Leukemia
Professor, Departments of Experimental Therapeutics & Leukemia
Chair Ad Interim, Department of Experimental Therapeutics
Faculty Liaison, Office of Postdoctoral Affairs and Development
Professor and Deputy Chair, Department of Leukemia
Center Medical Director, Leukemia Center
Executive Director, Inpatient Medical Operations
Ibrutinib and Venetoclax for First-Line Treatment of CLL
BACKGROUND: Ibrutinib, an inhibitor of Bruton’s tyrosine kinase, and venetoclax, an inhibitor of B-cell lymphoma 2 protein, have been approved for patients with chronic lymphocytic leukemia (CLL). Preclinical investigations have indicated potential synergistic interaction of their combination.
RESULTS: A total of 80 patients were treated. The median age was 65 years (range, 26 to 83). A total of 30% of the patients were 70 years of age or older. Overall, 92% of the patients had unmutated IGHV, TP53 aberration, or chromosome 11q deletion. With combined treatment, the proportions of patients who had complete remission (with or without normal blood count recovery) and remission with undetectable minimal residual disease increased over time. After 12 cycles of combined treatment, 88% of the patients had complete remission or complete remission with incomplete count recovery, and 61% had remission with undetectable minimal residual disease. Responses were noted in older adults and across all high-risk subgroups. Three patients had laboratory evidence of tumor lysis syndrome. The adverse-event profile was similar to what has been reported with ibrutinib and venetoclax.
CONCLUSIONS: In this study, combined venetoclax and ibrutinib was an effective oral regimen for highrisk and older patients with CLL. (Funded by AbbVie and others; ClinicalTrials. gov number, NCT02756897.)
Nitin Jain, Michael Keating, Philip Thompson, Alessandra Ferrajoli, Jan Burger, Gautam Borthakur, Koichi Takahashi, Zeev Estrov, Nathan Fowler, Tapan Kadia, Marina Konopleva, Yesid Alvarado, Musa Yilmaz, Courtney DiNardo, Prithviraj Bose, Maro Ohanian, Naveen Pemmaraju, Elias Jabbour, Koji Sasaki, Rashmi Kanaga-Shamanna, Keyur Patel, Jeffrey Jorgensen, Naveen Garg, Xuemei Wang, Katrina Sondermann, Nichole Cruz, Chongjuan Wei, Ana Ayala, William Plunkett, Hagop Kantarjian, Varsha Gandhi and William Wierda
Florencia McAllister, M.D.
Tumor Microbiome Diversity and Composition Influence Pancreatic Cancer Outcomes
Most patients diagnosed with resected pancreatic adenocarcinoma (PDAC) survive less than 5 years, but a minor subset survives longer. Here, we dissect the role of the tumor microbiota and the immune system in influencing long-term survival. Using 16S rRNA gene sequencing, we analyzed the tumor microbiome composition in PDAC patients with short-term survival (STS) and long-term survival (LTS). We found higher alpha-diversity in the tumor microbiome of LTS patients and identified an intra-tumoral microbiome signature (Pseudoxanthomonas-Streptomyces-Saccharopoly-spora-Bacillus clausii) highly predictive of long-term survivorship in both discovery and validation cohorts. Through human-into-mice fecal microbiota transplantation (FMT) experiments from STS, LTS, or control donors, we were able to differentially modulate the tumor microbiome and affect tumor growth as well as tumor immune infiltration. Our study demonstrates that PDAC microbiome composition, which cross-talks to the gut microbiome, influences the host immune response and natural history of the disease.
Erick Riquelme, Yu Zhang, Liangliang Zhang, Maria Montiel, Michelle Zoltan, Wenli Dong, Pompeyo Quesada, Ismet Sahin, Vidhi Chandra, Anthony San Lucas, Paul Scheet, Hanwen Xu, Samir M. Hanash, Lei Feng, Jared K.Burks, Kim-Anh Do, Christine B. Peterson, Deborah Nejman, Ching-Wei D. Tzeng, Michael P. Kim, Cynthia L. Sears, Nadim Ajami, Joseph Petrosino, Laura D. Wood, Anirban Maitra, Ravid Straussman, Matthew Katz, James Robert White, Robert Jenq, Jennifer Wargo and Florencia McAllister
Assistant Professor, Departments of Clinical Cancer Prevention & GI Medical Oncology
Xiaofei Zhou, Ph.D. & Shao-Cong Sun, Ph.D.
Instructor, Department of Immunology
Deputy Chair, Immuology
Professor, Department of Immunology
Administrative Director, South Campus Research Bldg
Moshe Talpaz Endowed Chair in Immunology
The deubiquitinase Otub1 controls the activation of CD8+ T cells and NK cells by regulating IL-15-mediated priming
CD8+ T cells and natural killer (NK) cells are central cellular components of immune responses against pathogens and cancer, which rely on interleukin (IL)-15 for homeostasis. Here we show that IL-15 also mediates homeostatic priming of CD8+ T cells for antigen-stimulated activation, which is controlled by a deubiquitinase, Otub1. IL-15 mediates membrane recruitment of Otub1, which inhibits ubiquitin-dependent activation of AKT, a kinase that is pivotal for T cell activation and metabolism. Otub1 deficiency in mice causes aberrant responses of CD8+ T cells to IL-15, rendering naive CD8+ T cells hypersensitive to antigen stimulation characterized by enhanced metabolic reprograming and effector functions. Otub1 also controls the maturation and activation of NK cells. Deletion of Otub1 profoundly enhances anticancer immunity by unleashing the activity of CD8+ T cells and NK cells. These findings suggest that Otub1 controls the activation of CD8+ T cells and NK cells by functioning as a checkpoint of IL-15-mediated priming.
Xiaofei Zhou, Jiayi Yu, Xuhong Cheng, Baoyu Zhao, Ganiraju C. Manyam, Li Zhang, Kimberly Schluns, Pingwei Li, Jing Wang and Shao-Cong Sun
• March - May 2019
Moran Amit, MD, Ph.D.
Journal of Clinical Oncology
Induction Chemotherapy Response as a Guide for Treatment Optimization in Sinonasal Undifferentiated Carcinoma
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Michael A. Davies, M.D., Ph.D.
Cancer Discovery
Molecular Profiling Reveals Unique Immune and Metabolic Features of Melanoma Brain Metastases
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Naveen Pemmaraju, M.D.
The New England Journal of Medicine
Tagraxofusp in Blastic Plasmacytoid Dendritic-Cell Neoplasm
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Y. Alan Wang, Ph.D. | Ronald A. DePinho, M.D.
Cancer Cell
KRAS-IRF2 Axis Drives Immune Suppression and Immune Therapy Resistance in Colorectal Cancer
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Lauren Averett Byers, M.D.
Cancer Discovery
Targeting DNA Damage Response Promotes Antitumor Immunity through STING-Mediated T-cell Activation in Small Cell Lung Cancer
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Jo Ishizawa, M.D., Ph.D. | Michael Andreeff, M.D., Ph.D.
Cancer Cell
Mitochondrial ClpP-Mediated Proteolysis Induces Selective Cancer Cell Lethality
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Jordi Rodon Ahnert, M.D., Ph.D. | Apostolia Maria Tsimberidou, M.D., Ph.D. | Jiun-Kae Jack Lee, Ph.D.
Nature Medicine
Genomic and transcriptomic profiling expands precision cancer medicine: the WINTHER trial
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Wangtong Yao, Ph.D. | Giulio Draetta, M.D., Ph.D.
Nature
Syndecan 1 is a critical mediator of macropinocytosis in pancreatic cancer
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Moran Amit, M.D., Ph.D.
Induction Chemotherapy Response as a Guide for Treatment Optimization in Sinonasal Undifferentiated Carcinoma
PURPOSE: Multimodal therapy is a well-established approach for the treatment of sinonasal undifferentiated carcinoma (SNUC); however, the optimal sequence of the various treatments modalities is yet to be determined. This study aimed to assess the role of induction chemotherapy (IC) in guiding definitive therapy in patients with SNUC.
METHODS: Ninety-five previously untreated patients diagnosed with SNUC and treated between 2001 and 2018 at The University of Texas MD Anderson Cancer Center were included in the analysis. Patients were treated with curative intent and received IC before definitive locoregional therapy. The primary end point was diseasespecific survival (DSS). Secondary end points included overall and disease-free survival, disease recurrence, and organ preservation.
RESULTS: A total of 95 treatment-naïve patients were included in the analysis. For the entire cohort, the 5-years DSS probability was 59% (95% CI, 53% to 66%). In patients who had partial or complete response to IC, the 5-year DSS probabilities were 81% (95% CI, 69% to 88%) after treatment with definitive concurrent chemoradiotherapy (CRT) after IC and 54% (95% CI, 44% to 61%) after definitive surgery and postoperative radiotherapy or CRT after IC (log-rank P = .001). In patients who did not experience at least a partial response to IC, the 5-year DSS probabilities were 0% (95% CI, 0% to 4%) in patients who were treated with concurrent CRT after IC and 39% (95% CI, 30% to 46%) in patients who were treated with surgery plus radiotherapy or CRT (adjusted hazard ratio of 5.68 [95% CI, 2.89 to 9.36]).
CONCLUSION: In patients who achieve a favorable response to IC, definitive CRT results in improved survival compared with those who undergo definitive surgery. In patients who do not achieve a favorable response to IC, surgery when feasible seems to provide a better chance of disease control and improved survival.
Moran Amit, M.D., Ph.D.; Ahmed S. Abdelmeguid, M.D.; Teemaranawich Watcherporn, M.D.; Hideaki Takahashi, M.D., Ph.D.; Samantha Tam, M.D.; Diana Bell, M.D.; Renata Ferrarotto, M.D.; Bonnie Glisson, M.D.; Michael E. Kupferman, M.D.; Dianna B. Roberts, Ph.D.; Shirley Y. Su; Shaan M. Raza, M.D.; Franco DeMonte, M.D. and Ehab Y. Hanna, M.D.
Assistant Professor, Department of Head & Neck Surgery
Lauren Averett Byers, M.D.
Associate Professor, Department of Thoracic/Head & Neck Medical Oncology
Targeting DNA Damage Response Promotes Antitumor Immunity through STING-Mediated T-cell Activation in Small Cell Lung Cancer
Despite recent advances in the use of immunotherapy, only a minority of patients with small cell lung cancer (SCLC) respond to immune checkpoint blockade (ICB). Here, we show that targeting the DNA damage response (DDR) proteins PARP and checkpoint kinase 1 (CHK1) significantly increased protein and surface expression of PD-L1. PARP or CHK1 inhibition remarkably potentiated the antitumor effect of PD-L1 blockade and augmented cytotoxic T-cell infiltration in multiple immunocompetent SCLC in vivo models. CD8+ T-cell depletion reversed the antitumor effect, demonstrating the role of CD8+ T cells in combined DDR–PD-L1 blockade in SCLC. We further demonstrate that DDR inhibition activated the STING/TBK1/IRF3 innate immune pathway, leading to increased levels of chemokines such as CXCL10 and CCL5 that induced activation and function of cytotoxic T lymphocytes. Knockdown of cGAS and STING successfully reversed the antitumor effect of combined inhibition of DDR and PD-L1. Our results define previously unrecognized innate immune pathway–mediated immunomodulatory functions of DDR proteins and provide a rationale for combining PARP/CHK1 inhibitors and immunotherapies in SCLC.
SIGNIFICANCE: Our results define previously unrecognized immunomodulatory functions of DDR inhibitors and suggest that adding PARP or CHK1 inhibitors to ICB may enhance treatment efficacy in patients with SCLC. Furthermore, our study supports a role of innate immune STING pathway in DDR-mediated antitumor immunity in SCLC.
Triparna Sen, B. Leticia Rodriguez, Limo Chen, Carminia M. Della Corte, Naoto Morikawa, Junya Fujimoto, Sandra Cristea, Thuyen Nguyen, Lixia Diao, Lerong Li, Youhong Fan, Yongbin Yang, Jing Wang, Bonnie S. Glisson, Ignacio I. Wistuba, Julien Sage, John V. Heymach, Don L. Gibbons and Lauren A. Byers
Michael A. Davies, M.D., Ph.D.
Molecular Profiling Reveals Unique Immune and Metabolic Features of Melanoma Brain Metastases
There is a critical need to improve our understanding of the pathogenesis of melanoma brain metastases (MBM). Thus, we performed RNA sequencing on 88 resected MBMs and 42 patient-matched extracranial metastases; tumors with sufficient tissue also underwent whole-exome sequencing, T-cell receptor sequencing, and IHC. MBMs demonstrated heterogeneity of immune infiltrates that correlated with prior radiation and post-craniotomy survival.
Comparison with patient-matched extracranial metastases identified significant immunosuppression and enrichment of oxidative phosphorylation (OXPHOS) in MBMs. Gene-expression analysis of intracranial and subcutaneous xenografts, and a spontaneous MBM model, confirmed increased OXPHOS gene expression in MBMs, which was also detected by direct metabolite profiling and [U-13C]-glucose tracing in vivo. IACS-010759, an OXPHOS inhibitor currently in early-phase clinical trials, improved survival of mice bearing MAPK inhibitor–resistant intracranial melanoma xenografts and inhibited MBM formation in the spontaneous MBM model. The results provide new insights into the pathogenesis and therapeutic resistance of MBMs.
SIGNIFICANCE: Improving our understanding of the pathogenesis of MBMs will facilitate the rational development and prioritization of new therapeutic strategies. This study reports the most comprehensive molecular profiling of patient-matched MBMs and extracranial metastases to date. The data provide new insights into MBM biology and therapeutic resistance.
Grant M. Fischer, Ali Jalali, David A. Kircher, Won-Chul Lee, Jennifer L. McQuade, Lauren E. Haydu, Aron Y. Joon, Alexandre Reuben, Mariana P. de Macedo, Fernando C. L. Carapeto, Chendong Yang, Anuj Srivastava, Chandrashekar R. Ambati, Arun Sreekumar, Courtney W. Hudgens, Barbara Knighton, Wanleng Deng, Sherise D. Ferguson, Hussein A. Tawbi, Isabella C. Glitza, Jeffrey E. Gershenwald, Y. N. Vashisht Gopal, Patrick Hwu, Jason T. Huse, Jennifer A. Wargo, P. Andrew Futreal, Nagireddy Putluri, Alexander J. Lazar, Ralph J. DeBerardinis, Joseph R. Marszalek, Jianjun Zhang, Sheri L. Holmen, Michael T. Tetzlaff and Michael A. Davies
Chair, Melanoma Medical Oncology
Professor, Departments of Melanoma Medical Oncology, Systems Biology & Translational Molecular Pathology
Jo Ishizawa, M.D., Ph.D. & Michael Andreeff, M.D., Ph.D.
Mitochondrial ClpP-Mediated Proteolysis Induces Selective Cancer Cell Lethality
The mitochondrial caseinolytic protease P (ClpP) plays a central role in mitochondrial protein quality control by degrading misfolded proteins. Using genetic and chemical approaches, we showed that hyperactivation of the protease selectively kills cancer cells, independently of p53 status, by selective degradation of its respiratory chain protein substrates and disrupts mitochondrial structure and function, while it does not affect non-malignant cells. We identified imipridones as potent activators of ClpP. Through biochemical studies and crystallography, we show that imipridones bind ClpP non-covalently and induce proteolysis by diverse structural changes. Imipridones are presently in clinical trials. Our findings suggest a general concept of inducing cancer cell lethality through activation of mitochondrial proteolysis.
Jo Ishizawa, Sarah F. Zarabi, R.Eric Davis, Ondrej Halgas, Takenobu Nii, Yulia Jitkova, Ran Zhao, Jonathan St-Germain, Lauren E. Heese, Grace Egan, Vivian R. Ruvolo, Samir H.Barghout, Yuki Nishida, Rose Hurren, Wencai Ma, Marcela Gronda, Todd Link, Keith Wong, Mark Mabanglo, Kensuke Kojima, Gautam Borthakur, Neil MacLean, Man Chun John Ma, Andrew B. Leber, Mark D. Minden, Walid Houry, Hagop Kantarjian, Martin Stogniew, Brian Raught, Emil F. Pai, Aaron D. Schimmer and Michael Andreeff
Assistant Professor, Department of Leukemia
Professor, Departments of Leukemia & Stem Cell Transplantation
Paul and Mary Haas Chair in Genetics
Naveen Pemmaraju, M.D.
Associate Professor, Department of Leukemia
Tagraxofusp in Blastic Plasmacytoid Dendritic-Cell Neoplasm
BACKGROUND: Blastic plasmacytoid dendritic-cell neoplasm (BPDCN) is an aggressive hematologic cancer that is caused by transformed plasmacytoid dendritic cells that overexpress interleukin-3 receptor subunit alpha (IL3RA or CD123). Tagraxofusp (SL-401) is a CD123-directed cytotoxin consisting of human interleukin-3 fused to truncated diphtheria toxin.
RESULTS: Of the 47 patients, 32 were receiving tagraxofusp as first-line treatment and 15 had received previous treatment. The median age of the patients was 70 years (range, 22 to 84). Among the 29 previously untreated patients who received tagraxofusp at a dose of 12 µg per kilogram, the primary outcome occurred in 21 (72%), and the overall response rate was 90%; of these patients, 45% went on to undergo stem-cell transplantation. Survival rates at 18 and 24 months were 59% and 52%, respectively. Among the 15 previously treated patients, the response rate was 67%, and the median overall survival was 8.5 months. The most common adverse events were increased levels of alanine aminotransferase (64%) and aspartate aminotransferase (60%), hypoalbuminemia (55%), peripheral edema (51%), and thrombocytopenia (49%). Capillary leak syndrome was reported in 19% of the patients and was associated with one death in each of the dose subgroups.
CONCLUSIONS: In adult patients with untreated or relapsed BPDCN, the use of tagraxofusp led to clinical responses. Serious adverse events included capillary leak syndrome; hepatic dysfunction and thrombocytopenia were common. (Funded by Stemline Therapeutics and the Leukemia and Lymphoma Society Therapy Acceleration Program; ClinicalTrials.gov number, NCT02113982.)
Naveen Pemmaraju, Andrew A. Lane, Kendra L. Sweet, Anthony S. Stein, Sumithira Vasu, William Blum, David A. Rizzieri, Eunice S. Wang, Madeleine Duvic, J. Mark Sloan, Sharon Spence, Shay Shemesh, Christopher L. Brooks, John Balser, Ivan Bergstein, Jeffrey E. Lancet, Hagop M. Kantarjian and Marina Konopleva
Jordi Rodon Ahnert, M.D., Ph.D., Apostolia Maria Tsimberidou, M.D., Ph.D. & Jiun-Kae Jack Lee, Ph.D.
Genomic and transcriptomic profiling expands precision cancer medicine: the WINTHER trial
Precision medicine focuses on DNA abnormalities, but not all tumors have tractable genomic alterations. The WINTHER trial (NCT01856296) navigated patients to therapy on the basis of fresh biopsy-derived DNA sequencing (arm A; 236 gene panel) or RNA expression (arm B; comparing tumor to normal). The clinical management committee (investigators from five countries) recommended therapies, prioritizing genomic matches; physicians determined the therapy given. Matching scores were calculated post-hoc for each patient, according to drugs received: for DNA, the number of alterations matched divided by the total alteration number; for RNA, expression-matched drug ranks. Overall, 303 patients consented; 107 (35%; 69 in arm A and 38 in arm B) were evaluable for therapy. The median number of previous therapies was three. The most common diagnoses were colon, head and neck, and lung cancers. Among the 107 patients, the rate of stable disease ≥6 months and partial or complete response was 26.2% (arm A: 23.2%; arm B: 31.6% (P=0.37)). The patient proportion with WINTHER versus previous therapy progression- free,survival ratio of >1.5 was 22.4%, which did not meet the pre-specified primary end point. Fewer previous therapies, better performance status and higher matching score correlated with longer progression-free survival (all P<0.05, multivariate). Our study shows that genomic and transcriptomic profiling are both useful for improving therapy recommendations and patient outcome, and expands personalized cancer treatment.
Jordi Rodon, Jean-Charles Soria, Raanan Berger, Wilson H. Miller, Eitan Rubin, Aleksandra Kugel, Apostolia Tsimberidou, Pierre Saintigny, Aliza Ackerstein, Irene Braña, Yohann Loriot, Mohammad Afshar,Vincent Miller, Fanny Wunder, Catherine Bresson, Jean-François Martini, Jacques Raynaud, John Mendelsohn, Gerald Batist, Amir Onn, Josep Tabernero, Richard Schilsky, Vladimir Lazar, J. Jack Lee and Razelle Kurzrock
Associate Professor, Departments of Investigational Cancer Therapeutics & Genomic Medicine Research
Associate Medical Director, Institute for Personalized Cancer Therapy
Clinical Co-Director, Precision Oncology Decision Support Team
Professor, Investigational Cancer Therapeutics
Past MD Anderson's official Representative and Head, Membership Committee of the WIN Consortium
Past Chair, Clinical Research Committee, American Society of Clinical Oncology
Associate Vice President, Quantitative Sciences
Professor, Department of Basic Science
John G. and Marie Stella Kenedy Memorial Foundation, Chair
Y. Alan Wang Ph.D. & Ronald A. DePinho, M.D.
Associate Professor, Department of Cancer Biology
Laboratory Director, DePinho Laboratory
Past President
Professor, Department of Cancer Biology
Harry Graves Burkhart III in Cancer Research, Chair
KRAS-IRF2 Axis Drives Immune Suppression and Immune Therapy Resistance in Colorectal Cancer
The biological functions and mechanisms of oncogenic KRASG12D (KRAS*) in resistance to immune check-point blockade (ICB) therapy are not fully understood. We demonstrate that KRAS* represses the expression of interferon regulatory factor 2 (IRF2), which in turn directly represses CXCL3 expression. KRAS*-mediated repression of IRF2 results in high expression of CXCL3, which binds to CXCR2 on myeloid-derived suppressor cells and promotes their migration to the tumor microenvironment. Anti-PD-1 resistance of KRAS*-expressing tumors can be overcome by enforced IRF2 expression or by inhibition of CXCR2. Colorectal cancer (CRC) showing higher IRF2 expression exhibited increased responsiveness to anti-PD-1 therapy. The KRAS*-IRF2-CXCL3- CXCR2 axis provides a framework for patient selection and combination therapies to enhance the effectiveness of ICB therapy in CRC.
Wenting Liao, Michael J Overman, Adam T Boutin, Xiaoying Shang, Di Zhao, Prasenjit Dey, Jiexi Li, Guocan Wang, Zhengdao Lan, Jun Li, Ming Tang, Shan Jiang, Xingdi Ma, Peiwen Chen, Riham Katkhuda, Krittiya Korphaisarn, Deepavali Chakravarti, Andrew Chang, Denise J Spring, Qing Chang, Jianhua Zhang, Dipen M Maru, Dean Y Maeda, John A Zebala, Scott Kopetz, Y Alan Wang and Ronald A DePinho
Wangtong Yao, Ph.D. & Giulio Draetta, M.D., Ph.D.
Assistant Professor, Department of Translational Molecular Pathology
Senior Vice President, Chief Scientific Officer
Professor, Departments of Genomic Medicine Research and Molecular & Cellular Oncology
Sewell Family in Genomic Medicine, Chair
Syndecan 1 is a critical mediator of macropinocytosis in pancreatic cancer
Pancreatic ductal adenocarcinoma (PDAC) remains recalcitrant to all forms of cancer treatment and carries a five-year survival rate of only 8%1. Inhibition of oncogenic KRAS (hereafter KRAS*), the earliest lesion in disease development that is present in more than 90% of PDACs, and its signalling surrogates has yielded encouraging preclinical results with experimental agents2–4. However, KRAS*-independent disease recurrence following genetic extinction of Kras* in mouse models anticipates the need for co-extinction strategies5,6. Multiple oncogenic processes are initiated at the cell surface, where KRAS* physically and functionally interacts to direct signalling that is essential for malignant transformation and tumour maintenance. Insights into the complexity of the functional cellsurface-protein repertoire (surfaceome) have been technologically limited until recently and—in the case of PDAC—the genetic control of the function and composition of the PDAC surfaceome in the context of KRAS* signalling remains largely unknown. Here we develop an unbiased, functional target-discovery platform to query KRAS*-dependent changes of the PDAC surfaceome, which reveals syndecan 1 (SDC1, also known as CD138) as a protein that is upregulated at the cell surface by KRAS*. Localization of SDC1 at the cell surface—where it regulates macropinocytosis, an essential metabolic pathway that fuels PDAC cell growth—is essential for disease maintenance and progression. Thus, our study forges a mechanistic link between KRAS* signalling and a targetable molecule driving nutrient salvage pathways in PDAC and validates oncogene-driven surfaceome annotation as a strategy to identify cancer-specific vulnerabilities.
Wantong Yao, Johnathon L. Rose, Wei Wang, Sahil Seth, Hong Jiang, Ayumu Taguchi, Jintan Liu, Liang Yan, Avnish Kapoor, Pingping Hou, Ziheng Chen, Qiuyun Wang, Luigi Nezi, Zhaohui Xu, Jun Yao, Baoli Hu, Piergiorgio F. Pettazzoni, I Lin Ho, Ningping Feng, Vandhana Ramamoorthy, Shan Jiang, Pingna Deng, Grace J. Ma, Peter Den, Zhi Tan, Shu Xing Zhang, Huamin Wang, Y. Alan Wang, Angela K. Deem, Jason B. Fleming, Alessandro Carugo, Timothy P. Heffernan, Anirban Maitra, Andrea Viale, Haoqiang Ying, Samir Hanash, Ronald A. DePinho and Giulio F. Draetta
Sitting : Giulio Draetta, Wantong Yao, Hong Jiang
• December 2018 - February 2019
Shaobo Dai, Ph.D | Xiaodong Cheng, Ph.D.
Nature
SETD3 is an actin histidine methyltransferase that prevents primary dystocia
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Li Ma, Ph.D.
Nature Genetics
Long noncoding RNA MALAT1 suppresses breast cancer metastasis
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Yinghong Wang, M.D., Ph.D. | Beth Helmink, M.D., Ph.D.
Nature Medicine
Fecal microbiota transplantation for refractory immune checkpoint inhibitor-associated colitis
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Simone Hausmann, Ph.D. | Pawel K. Mazur, Ph.D.
Cell
METTL13 Methylation of eEF1A Increases Translational Output to Promote Tumorigenesis
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Nizar Tannir, M.D., F.A.C.P. | Giulio Draetta, M.D. | Ph.D., Giannicola Genovese, M.D.
Cancer Cell
p53 Is a Master Regulator of Proteostasis in SMARCB1-Deficient Malignant Rhabdoid Tumors
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Shaobo Dai, Ph.D. & Xiaodong Cheng, Ph.D
SETD3 is an actin histidine methyltransferase that prevents primary dystocia
For more than 50 years, the methylation of mammalian actin at histidine 73 has been known to occur. Despite the pervasiveness of His73 methylation, which we find is conserved in several model animals and plants, its function remains unclear and the enzyme that generates this modification is unknown. Here we identify SET domain protein 3 (SETD3) as the physiological actin His73 methyltransferase. Structural studies reveal that an extensive network of interactions clamps the actin peptide onto the surface of SETD3 to orient His73 correctly within the catalytic pocket and to facilitate methyl transfer. His73 methylation reduces the nucleotide-exchange rate on actin monomers and modestly accelerates the assembly of actin filaments. Mice that lack SETD3 show complete loss of actin His73 methylation in several tissues, and quantitative proteomics analysis shows that actin His73 methylation is the only detectable physiological substrate of SETD3. SETD3-deficient female mice have severely decreased litter sizes owing to primary maternal dystocia that is refractory to ecbolic induction agents. Furthermore, depletion of SETD3 impairs signal-induced contraction in primary human uterine smooth muscle cells. Together, our results identify a mammalian histidine methyltransferase and uncover a pivotal role for SETD3 and actin His73 methylation in the regulation of smooth muscle contractility. Our data also support the broader hypothesis that protein histidine methylation acts as a common regulatory mechanism.
Alex W. Wilkinson, Jonathan Diep, Shaobo Dai, Shuo Liu, Yaw Shin Ooi, Dan Song, Tie-Mei Li, John R. Horton, Xing Zhang, Chao Liu, Darshan V. Trivedi, Katherine M. Ruppel, José G. Vilches-Moure, Kerriann M. Casey, Justin Mak, Tina Cowan, Joshua E. Elias, Claude M. Nagamine, James A. Spudich, Xiaodong Cheng, Jan E. Carette and Or Gozani
Postdoctoral Fellow, Department of Epigenetics and Molecular Carcinogenesis
Professor, Department of Epigenetics and Molecular Carcinogenesis
Simone Hausmann, Ph.D. & Pawel K. Mazur, Ph.D.
METTL13 Methylation of eEF1A Increases Translational Output to Promote Tumorigenesis
Increased protein synthesis plays an etiologic role in diverse cancers. Here, we demonstrate that METTL13 (methyltransferase-like 13) dimethylationof eEF1A (eukaryotic elongation factor 1A) lysine55 (eEF1AK55me2) is utilized by Ras-driven cancers to increase translational output and promotetumorigenesis in vivo. METTL13-catalyzed eEF1A methylation increases eEF1A's intrinsic GTPase activity in vitro and protein production in cells. METTL13 and eEF1AK55me2 levels are upregulated in cancer and negatively correlate with pancreatic and lung cancer patient survival. METTL13 deletion and eEF1AK55me2 loss dramatically reduce Ras-driven neoplastic growth in mouse models and in patient-derived xenografts(PDXs) from primary pancreatic and lung tumors. Finally, METTL13 depletion renders PDX tumors hypersensitive to drugs that target growth-signaling pathways. Together, our work uncovers a mechanism by which lethal cancers become dependent on the METTL13-eEF1AK55me2 axis to meet their elevated protein synthesis requirement and suggests that METTL13 inhibition may constitute a targetable vulnerability of tumors driven by aberrant Ras signaling.
Shuo Liu, Simone Hausmann, Scott Moore Carlson, Mary Esmeralda Fuentes, Joel William Francis, Renjitha Pillai, Shane Michael Lofgren, Laura Hulea, Kristofferson Tandoc, Jiuwei Lu, Ami Li, Nicholas Dang Nguyen, Marcello Caporicci, Michael Paul Kim, Anirban Maitra, Huamin Wang, Ignacio Ivan Wistuba, John Anthony Porco Jr., Michael Cory Bassik, Joshua Eric Elias, Jikui Song, Ivan Topisirovic, Capucine Van Rechem, Pawel Karol Mazur and Or Gozani
Postdoctoral Fellow, Department of Experimental Radiation Oncology
Assistant Professor, Department of Experimental Radiation Oncology
Li Ma, Ph.D.
Associate Professor, Department of Experimental Radiation Oncology
Long noncoding RNA MALAT1 suppresses breast cancer metastasis
MALAT1 has previously been described as a metastasis-promoting long noncoding RNA (lncRNA). We show here, however, that targeted inactivation of the Malat1 gene in a transgenic mouse model of breast cancer, without altering the expression of its adjacent genes, promotes lung metastasis, and that this phenotype can be reversed by genetic add-back of Malat1. Similarly, knockout of MALAT1 in human breast cancer cells induces their metastatic ability, which is reversed by re-expression of Malat1. Conversely, overexpression of Malat1 suppresses breast cancer metastasis in transgenic, xenograft, and syngeneic models. Mechanistically, the MALAT1 lncRNA binds and inactivates the prometastatic transcription factor TEAD, preventing TEAD from associating with its co-activator YAP and target gene promoters. Moreover, MALAT1 levels inversely correlate with breast cancer progression and metastatic ability. These findings demonstrate that MALAT1 is a metastasis-suppressing lncRNA rather than a metastasis promoter in breast cancer, calling for rectification of the model for this highly abundant and conserved lncRNA.
Jongchan Kim, Hai-Long Piao, Beom-Jun Kim, Fan Yao, Zhenbo Han, Yumeng Wang, Zhenna Xiao, Ashley N. Siverly, Sarah E. Lawhon, Baochau N. Ton, Hyemin Lee, Zhicheng Zhou, Boyi Gan, Shinichi Nakagawa, Matthew J. Ellis, Han Liang, Mien-Chie Hung, M. James You, Yutong Sun and Li Ma
Nizar Tannir, M.D., F.A.C.P., Giulio Draetta, M.D., Ph.D. & Giannicola Genovese, M.D.
Professor and Chair ad interim , Department of Genitourinary Medical Oncology
Ransom Horne, Jr. Professorship for Cancer Research
Senior Vice President, Chief Scientific Officer
Professor, Departments of Genomic Medicine Research and Molecular & Cellular Oncology
Sewell Family in Genomic Medicine, Chair
Assistant Professor, Departments of Genitourinary Medical Oncology and Genomic Medicine Research
p53 Is a Master Regulator of Proteostasis in SMARCB1-Deficient Malignant Rhabdoid Tumors
Alterations in chromatin remodeling genes have been increasingly implicated in human oncogenesis. Specifically, the biallelic inactivation of the SWI/SNF subunit SMARCB1 results in the emergence of extremely aggressive pediatric malignancies. Here, we developed embryonic mosaic mouse models of malignant rhabdoid tumors (MRTs) that faithfully recapitulate the clinical- pathological features of the human disease. We demonstrated that SMARCB1-deficient malignancies exhibit dramatic activation of the unfolded protein response (UPR) and ER stress response via a genetically intact MYC-p19ARF-p53 axis. As a consequence, these tumors display an exquisite sensitivity to agents inducing proteotoxic stress and inhibition of the autophagic machinery. In conclusion, our findings provide a rationale for drug repositioning trials investigating combinations of agents targeting the UPR and autophagy in SMARCB1-deficient MRTs.
Alessandro Carugo, Rosalba Minelli, Luigi Sapio, Melinda Soeung, Federica Carbone, Frederick S. Robinson, James Tepper, Ziheng Chen, Sara Lovisa, Maria Svelto, Samirkumar Amin, Sanjana Srinivasan, Edoardo Del Poggetto, Sara Loponte, Francesca Puca, Prasenjit Dey, Gabriel G. Malouf, Xiaoping Su, Liren Li, Dolores Lopez-Terrada, Dinesh Rakheja, Alexander J. Lazar, George J. Netto, Priya Rao, Alessandro Sgambato, Anirban Maitra, Durga N. Tripathi, Cheryl L. Walker, Jose A. Karam, Timothy P. Heffernan, Andrea Viale, Charles W.M. Roberts, Pavlos Msaouel, Nizar M. Tannir, Giulio F. Draetta and Giannicola Genovese
Yinghong Wang, M.D., Ph.D. & Beth Helmink, M.D., Ph.D.
Fecal microbiota transplantation for refractory immune checkpoint inhibitor-associated colitis
We report the first case series of immune checkpoint inhibitors (ICI)-associated colitis successfully treated with fecal microbiota transplantation, with reconstitution of the gut microbiome and a relative increase in the proportion of regulatory T-cells within the colonic mucosa. These preliminary data provide evidence that modulation of the gut microbiome may abrogate ICI-associated colitis.
Yinghong Wang, Diana H. Wiesnoski, Beth A. Helmink, Vancheswaran Gopalakrishnan, Kati Choi, Hebert L. DuPont, Zhi-Dong Jiang, Hamzah Abu-Sbeih, Christopher A. Sanchez, Chia-Chi Chang, Edwin R. Parra, Alejandro Francisco-Cruz, Gottumukkala S. Raju, John R. Stroehlein, Matthew T. Campbell, Jianjun Gao, Sumit K. Subudhi, Dipen M. Maru, Jorge M. Blando, Alexander J. Lazar, James P. Allison, Padmanee Sharma, Michael T. Tetzlaff, Jennifer A. Wargo and Robert R. Jenq
Back row L to R : Alexander Lazar, Gottumukkala Subba Raju, Jennifer Wargo, Robert Jenq, Chia-Chi Chang
Associate Professor, Department of Gastroenterology Hepatology & Nutrition
Fellow, Department of Surgical Oncology
• September - November 2018
Camilo Jimenez, M.D.
Journal of Nuclear Medicine
Efficacy and Safety of High-Specific-Activity I-131 MIBG Therapy in Patients with Advanced Pheochromocytoma or Paraganglioma
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Katy Rezvani, M.D., Ph.D.
The New England Journal of Medicine
Allogeneic BK Virus–Specific T Cells for Progressive Multifocal Leukoencephalopathy
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Koichi Takahashi, M.D., Ph.D.
Cell Stem Cell
PPM1D Mutations Drive Clonal Hematopoiesis in Response to Cytotoxic Chemotherapy
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Don Lynn Gibbons, M.D., Ph.D.
CD38-Mediated Immunosuppression as a Mechanism of Tumor Cell Escape from PD-1/PD-L1 Blockade
Although treatment with immune checkpoint inhibitors provides promising benefit for patients with cancer, optimal use is encumbered by high resistance rates and requires a thorough understanding of resistance mechanisms. We observed that tumors treated with PD-1/PD-L1 blocking antibodies develop resistance through the upregulation of CD38, which is induced by all-trans retinoic acid and IFNβ in the tumor microenvironment. In vitro and in vivo studies demonstrate that CD38 inhibits CD8+ T-cell function via adenosine receptor signaling and that CD38 or adenosine receptor blockade are effective strategies to overcome the resistance. Large data sets of human tumors reveal expression of CD38 in a subset of tumors with high levels of basal or treatment-induced T-cell infiltration, where immune checkpoint therapies are thought to be most effective. These findings provide a novel mechanism of acquired resistance to immune checkpoint therapy and an opportunity to expand their efficacy in cancer treatment.
SIGNIFICANCE: CD38 is a major mechanism of acquired resistance to PD-1/PD-L1 blockade, causing CD8+ T-cell suppression. Coinhibition of CD38 and PD-L1 improves antitumor immune response. Biomarker assessment in patient cohorts suggests that a combination strategy is applicable to a large percentage of patients in whom PD-1/PD-L1 blockade is currently indicated.
Limo Chen, Lixia Diao, Yongbin Yang, Xiaohui Yi, B. Leticia Rodriguez, Yanli Li, Pamela A. Villalobos, Tina Cascone, Xi Liu, Lin Tan, Philip L. Lorenzi, Anfei Huang, Qiang Zhao, Di Peng, Jared J. Fradette, David H. Peng, Christin Ungewiss, Jonathon Roybal, Pan Tong, Junna Oba, Ferdinandos Skoulidis, Weiyi Peng, Brett W. Carter, Carl M. Gay, Youhong Fan, Caleb A. Class, Jingfen Zhu, Jaime Rodriguez-Canales, Masanori Kawakami, Lauren Averett Byers, Scott E. Woodman, Vassiliki A. Papadimitrakopoulou, Ethan Dmitrovsky, Jing Wang, Stephen E. Ullrich, Ignacio I. Wistuba, John V. Heymach, F. Xiao-Feng Qin and Don L. Gibbons
Associate Professor, Departments of Thoracic/Head and Neck Medical Oncology and Molecular & Cellular Oncology
Director, Director THNMO Translational Genetic Models Laboratory
Camilo Jimenez, M.D.
Professor, Department of Endocrine Neoplasia and Hormonal Disorders
Back left to right : Bill Erwin, M.D., Mouhammed Habra, M.D.
Efficacy and Safety of High-Specific-Activity 131I-MIBG Therapy in Patients with Advanced Pheochromocytoma or Paraganglioma
Patients with metastatic or unresectable (advanced) pheochromocytoma or paraganglioma (PPGL) have poor prognoses and few treatment options. This multicenter, phase 2 trial evaluated the efficacy and safety of high-specific-activity 131I-meta-iodobenzylguanidine (HSA 131I-MIBG) in patients with advanced PPGL.
METHODS: In this open-label, single-arm study, 81 PPGL patients were screened for enrollment, and 74 received a treatment-planning dose of HSA 131I-MIBG. 68 patients with advanced PPGL received at least one therapeutic dose (~18.5 GBq) of HSA 131I-MIBG intravenously. The primary endpoint was the proportion of patients with at least a 50% reduction in baseline antihypertensive medication use lasting at least 6 months. Secondary endpoints included objective tumor response as assessed by Response Evaluation Criteria in Solid Tumors version 1.0; biochemical tumor marker response; overall survival (OS); and safety.
RESULTS: Of the 68 patients who received at least one therapeutic dose of HSA 131I-MIBG, 17 (25%; 95% CI, 16-37%) had a durable reduction in baseline antihypertensive medication use. Among 64 patients with evaluable disease, 59 (92%) had a partial response or stable disease as the best objective response within 12 months. Decreases in elevated (≥1.5 times the upper limit of normal at baseline) serum chromogranin levels were observed with confirmed complete and partial responses 12 months after treatment in 19 of 28 patients (68%). The median OS duration was 36.7 months (95% CI, 29.9-49.1 months). The most common treatment-emergent adverse events were nausea, myelosuppression, and fatigue. No patients had drug-related acute hypertensive events during or after the administration of HSA 131I-MIBG.
CONCLUSION: HSA 131I-MIBG offers multiple benefits, including sustained blood pressure control and tumor response in PPGL patients.
Daniel A. Pryma, Bennett B. Chin, Richard B. Noto, Joseph S. Dillon, Stephanie Perkins, Lilja Solnes, Lale Kostakoglu, Aldo N. Serafini, Miguel H. Pampaloni, Jessica Jensen, Thomas Armor, Tess Lin, Theresa White, Nancy Stambler, Stuart Apfel, Vincent A. DiPippo, Syed Mahmood, Vivien Wong and Camilo Jimenez
Pedro Tomas Ramirez, M.D.
Minimally Invasive versus Abdominal Radical Hysterectomy for Cervical Cancer
BACKGROUND: There are limited data from retrospective studies regarding whether survival outcomes after laparoscopic or robot-assisted radical hysterectomy (minimally invasive surgery) are equivalent to those after open abdominal radical hysterectomy (open surgery) among women with early-stage cervical cancer.
RESULTS: A total of 319 patients were assigned to minimally invasive surgery and 312 to open surgery. Of the patients who were assigned to and underwent minimally invasive surgery, 84.4% underwent laparoscopy and 15.6% robot-assisted surgery. Overall, the mean age of the patients was 46.0 years. Most patients (91.9%) had stage IB1 disease. The two groups were similar with respect to histologic subtypes, the rate of lymphovascular invasion, rates of parametrial and lymph-node involvement, tumor size, tumor grade, and the rate of use of adjuvant therapy. The rate of disease-free survival at 4.5 years was 86.0% with minimally invasive surgery and 96.5% with open surgery, a difference of -10.6 percentage points (95% confidence interval [CI], -16.4 to -4.7). Minimally invasive surgery was associated with a lower rate of disease-free survival than open surgery (3-year rate, 91.2% vs. 97.1%; hazard ratio for disease recurrence or death from cervical cancer, 3.74; 95% CI, 1.63 to 8.58), a difference that remained after adjustment for age, body-mass index, stage of disease, lymphovascular invasion, and lymph-node involvement; minimally invasive surgery was also associated with a lower rate of overall survival (3-year rate, 93.8% vs. 99.0%; hazard ratio for death from any cause, 6.00; 95% CI, 1.77 to 20.30).
CONCLUSION: In this trial, minimally invasive radical hysterectomy was associated with lower rates of disease-free survival and overall survival than open abdominal radical hysterectomy among women with early-stage cervical cancer.
Pedro T. Ramirez, Michael Frumovitz, Rene Pareja, Aldo Lopez, Marcelo Vieira, Reitan Ribeiro, Alessandro Buda, Xiaojian Yan, Yao Shuzhong, Naven Chetty, David Isla, Mariano Tamura, Tao Zhu, Kristy P. Robledo, Val Gebski, Rebecca Asher, Vanessa Behan, James L. Nicklin, Robert L. Coleman and Andreas Obermair
Professor, Department of Gynecological Oncology & Reproductive Medicine
David M. Gershenson, M.D., Distinguished Professorship for Ovarian Cancer Research
Katy Rezvani, M.D., Ph.D.
Professor, Department of Stem Cell Transplantation
Chief, Section of Cellular Therapy
Medical Director, GMP Cell Therapy Laboratory
Director, Translational Research
Allogeneic BK Virus–Specific T Cells for Progressive Multifocal Leukoencephalopathy
JC virus, the cause of progressive multifocal leukoencephalopathy (PML), and the BK virus are genetically similar and share sequence homology in immunogenic proteins. We treated three immunosuppressed patients with PML with ex vivo–expanded, partially HLA-matched, third-party–produced, cryopreserved BK virus–specific T cells. The immunosuppression in these patients was due to the conditioning regimen for cord-blood transplantation in one patient, a myeloproliferative neoplasm treated with ruxolitinib in another, and acquired immunodeficiency syndrome in the third. After T-cell infusion in two of the patients, alleviation of the clinical signs and imaging features of PML was seen and JC virus in the cerebrospinal fluid (CSF) cleared. The other patient had a reduction in JC viral load and stabilization of symptoms that persisted until her death 8 months after the first infusion. Two of the patients had immune reconstitution syndrome. Donor-derived T cells were detected in the CSF after infusion.
(Funded by the M.D. Anderson Cancer Center Moon Shots Program and the National Institutes of Health; ClinicalTrials. gov number, NCT02479698.)
Muharrem Muftuoglu, Amanda Olson, David Marin, Sairah Ahmed, Victor Mulanovich, Sudhakar Tummala, T. Linda Chi, Alessandra Ferrajoli, Indreshpal Kaur, Li Li, Richard Champlin, Elizabeth J. Shpall and Katayoun Rezvani
Koichi Takahashi, M.D., Ph.D.
Assistant Professor, Departments of Leukemia and Genomic Medicine
PPM1D Mutations Drive Clonal Hematopoiesis in Response to Cytotoxic Chemotherapy
Clonal hematopoiesis (CH), in which stem cell clones dominate blood production, becomes increasingly common with age and can presage malignancy development. The conditions that promote ascendancy of particular clones are unclear. We found that mutations in PPM1D (protein phosphatase Mn2+/Mg2+-dependent 1D), a DNA damage response regulator that is frequently mutated in CH, were present in one-fifth of patients with therapy-related acute myeloid leukemia or myelodysplastic syndrome and strongly correlated with cisplatin exposure. Cell lines with hyperactive PPM1D mutations expand to outcompete normal cells after exposure to cytotoxic DNA damaging agents including cisplatin, and this effect was predominantly mediated by increased resistance to apoptosis. Moreover, heterozygous mutant Ppm1d hematopoietic cells outcompeted their wild-type counterparts in vivo after exposure to cisplatin and doxorubicin, but not during recovery from bone marrow transplantation. These findings establish the clinical relevance of PPM1D mutations in CH and the importance of studying mutation-treatment interactions.
Joanne I. Hsu, Tajhal Dayaram, Ayala Tovy, Etienne De Braekeleer, Mira Jeong, Feng Wang, Jianhua Zhang, Timothy P. Heffernan, Sonal Gera, Jeffrey J. Kovacs, Joseph R. Marszalek, Christopher Bristow, Yuanqing Yan, Guillermo Garcia-Manero, Hagop Kantarjian, George Vassiliou, P. Andrew Futreal, Lawrence A. Donehower, Koichi Takahashi and Margaret A. Goodell