Paul S. Mischel, Ludwig Institute for Cancer Research, San Diego
Paul S.
Mischel
Signaling, Tumor biology
Bio

I am a physician scientist with expertise in molecular pathology, signal transduction and cancer biology.

After my clinical residency and fellowship in anatomic pathology and neuropathology, I trained in molecular and cellular developmental neurobiology in Lou Reichardt’s lab at HHMI/UCSF and joined the faculty of UCLA in 1998. As a pathologist diagnosing patients’ tumor samples in the clinic, I became convinced that the key to improved care depends on extracting the essential molecular and biochemical information contained within these tumors and developing a deeper understanding of how the functional networks activated by these molecular lesions actually work. Over the past 15 years we have developed a research program that tightly integrates studies in pre-clinical models with analyses of patients treated in state-of-the-art clinical trials, with the goal of developing more effective, less toxic therapies. In August 2012 I joined the Ludwig Institute for Cancer Research, and I am delighted to have this opportunity to work with this extraordinary and highly collaborative group of colleagues.

Education
Post-doctoral Fellowship, Louis F. Reichardt’s laboratory, HHMI, UCSF, 1998

Residency in Anatomic Pathology and Neuropathology, UCLA, 1996

Cornell University Medical College, MD, 1991

University of Pennsylvania, BA, Philosophy, 1984


Achievements

Alpha Omega Alpha, Cornell University Medical College, 1991

Pfizer New Faculty Award (one in Neuroscience in United States), 1996

The Johnny Mercer Foundation Research Award, 2004

America’s Top Doctors for Cancer (Castle Connolly and US News and World Report), 2006-present

Farber Award (top brain tumor research award given jointly by the American Association of Neurological Surgeons and the Society for NeuroOncology), 2007

American Society for Clinical Investigation, 2007

Profiled by Journal of Cell Biology in the “People and Ideas” section, 2008

President, American Society for Clinical Investigation, 2011

American Association of Physicians, 2012

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Paul S. Mischel lab

Our laboratory aims to transform the care of patients with glioblastoma, the most common form of adult brain cancer, through molecular medicine. We use a combination of genetic and functional approaches to better understand the signaling and biochemical networks that are altered in glioblastoma with the goal of developing more effective, less toxic treatments.

Paul S. Mischel, Ludwig Institute for Cancer Research, San Diego
Paul S.
Mischel
Signaling, Tumor biology
Bio

I am a physician scientist with expertise in molecular pathology, signal transduction and cancer biology.

After my clinical residency and fellowship in anatomic pathology and neuropathology, I trained in molecular and cellular developmental neurobiology in Lou Reichardt’s lab at HHMI/UCSF and joined the faculty of UCLA in 1998. As a pathologist diagnosing patients’ tumor samples in the clinic, I became convinced that the key to improved care depends on extracting the essential molecular and biochemical information contained within these tumors and developing a deeper understanding of how the functional networks activated by these molecular lesions actually work. Over the past 15 years we have developed a research program that tightly integrates studies in pre-clinical models with analyses of patients treated in state-of-the-art clinical trials, with the goal of developing more effective, less toxic therapies. In August 2012 I joined the Ludwig Institute for Cancer Research, and I am delighted to have this opportunity to work with this extraordinary and highly collaborative group of colleagues.

Education
Post-doctoral Fellowship, Louis F. Reichardt’s laboratory, HHMI, UCSF, 1998

Residency in Anatomic Pathology and Neuropathology, UCLA, 1996

Cornell University Medical College, MD, 1991

University of Pennsylvania, BA, Philosophy, 1984


Achievements

Alpha Omega Alpha, Cornell University Medical College, 1991

Pfizer New Faculty Award (one in Neuroscience in United States), 1996

The Johnny Mercer Foundation Research Award, 2004

America’s Top Doctors for Cancer (Castle Connolly and US News and World Report), 2006-present

Farber Award (top brain tumor research award given jointly by the American Association of Neurological Surgeons and the Society for NeuroOncology), 2007

American Society for Clinical Investigation, 2007

Profiled by Journal of Cell Biology in the “People and Ideas” section, 2008

President, American Society for Clinical Investigation, 2011

American Association of Physicians, 2012

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TEAM

Ivan
Babic
Bio

My research focus is to understand how aberrant signal transduction in brain cancer regulates genome-wide changes in gene expression and RNA splicing, and how this ultimately influences cell metabolism and tumor growth.

Education
PhD, University of Calgary, Faculty of Medicine, Department of Biochemistry and Molecular Biology, 2005

Postdoctoral Fellow with Dr. Douglas Black, Department of Microbiology, Immunology and Molecular Genetics, University of California Los Angeles, 2005-09

Awards
Postdoctoral fellowship awarded by the Alberta Heritage Foundation for Medical Research, 2005-08

Doctoral Research Award, Canadian Institutes of Health Research, 2001-04

Yuchao (Jessica)
Gu
Bio

I’m interested in studying how mTOR inhibition affects metabolism in glioblastoma and am trying to identify additional drug targets involved in the metabolic pathways to overcome the resistance to mTOR inhibitors for the treatment of GBM.

Education
BS, Sun Yat-sen University School of Pharmaceutical Sciences, 2006-10

PhD candidate, University of California, Los Angeles, School of Medicine, Department of Molecular and Medical Pharmacology, 2010

Feng
Liu
Gene regulation
Bio

My work centers on the interface of genetic and epigenetic regulation of gene expression in the context of brain tumor cells. Specifically, I am using histone modification marks to map the cis-regulatory elements (e.g., enhancers and promoters) responding to oncogenic signaling pathways. By analyzing the composition and function of these elements, I’m aiming to identify the factors essential for initiating and maintaining tumor cell specific gene expression program.

Education
PhD, Neuroscience, University of Southern California, 2007

BS, Biochemistry and Molecular Biology, Peking University, China, 2000

Kristen
Turner
Bio

Glioblastoma (GBM) is among the most difficult cancers to treat and is characterized by marked resistance to therapeutic intervention. An important hallmark of GBM is the frequent activation of multiple receptor tyrosine kinases, including EGFR. However, success from single-agent kinase intervention remains limited. Tumor cells are capable of inducing a series of mechanisms by which they eventually escape the initial targeted inhibition, thereby causing the tumor to relapse. We are interested in understanding these mechanisms in both populations of tumor cells and at the single-cell level. Elucidating the underpinnings of therapeutic resistance is critical for success in combating this disease.

Education
PhD, Cancer Biology, doctoral dissertation performed in Wei Zhang’s laboratory, University of Texas Health Science Center at Houston, Graduate School of Biomedical Sciences, University of Texas, M.D. Anderson Cancer Center, 2012

MS, Biology, thesis work performed in Brenda Rodger’s laboratory, West Texas A&M University, 2006

BS, Biology/Chemistry, West Texas A&M University, 2003

Huijun
Yang
Bio

My role in the lab is to provide administrative and experimental research support and to help principal investigators create an environment where members of the lab can work together as an effective team. I aim to provide daily technical assistance for studies on the molecular pathogenesis of brain tumors; in the development of diagnostic molecular studies to select patients for brain tumor therapies; and in immunohistochemical analysis of signal pathways in brain tumor biopsies. I also am responsible for documenting all records and results.

Education
MS, Plant Molecular and Cell Biology, Capital Normal University, China, 1997

BS, Biology, Hebei Normal University, China, 1992

Beatrice
Gini
Bio

My focus is on the dissection, at single-cell level, of the molecular response of Glioblastoma cells to targeted therapies affecting the EGF receptor signaling. The objective is to clarify the intra-cellular network heterogeneity involved in the onset of therapy resistance so we can tailor synergistic and patient specific treatments. The project leverages the Mischel Lab's expertise on the EGFR pathway and on the collaboration with the Heath Lab at CalTech (Pasadena, USA).

Education
Post-doctoral work, Ludwig Institute for Cancer Research at the University of California San Diego, Molecular Pathology Lab, 2007-13

Post-doctoral work, Mischel Lab, Pathology and Molecular Medicine Department, University of California, Los Angeles, 2009

PhD, Neuroscience, University of Verona, Italy, 2008

Master's degree, Biotechnology, University of Verona, Italy, 2005

Awards
International Outgoing Fellowship from the European Union, 2011

CooperInt International Award, University of Verona, Italy, 2009

CooperInt International Award, University of Verona, Italy, 2008

Shiro
Ikegami
Bio

I am neurosurgeon from Japan. I did my PhD training with the goal of developing computer systems that could interact with the brain of patients with neurological disease. This work was designed to develop assistive technologies for patients with impaired movement. My clinical work will focus on the surgical and medical management of patients with brain tumors, and I joined the Mischel laboratory to work on understanding the molecular and biochemical consequences of altered signaling networks, with the goal of developing more effective targeted therapies.

PhD, Medicine, Chiba University Graduate School of Medicine, Japan, 2012

MD, Chiba University School of Medicine, Japan, 2002

Kenta
Masui
Bio

I am a neuropathologist from Japan and have received extensive clinical training. My research focuses on the molecular and pathological analyses on the biology of glioblastoma (GBM), one of the most malignant tumors in humans. I studying how mTOR signaling can potentially facilitate the metabolic adaptation and therapeutic resistance of GBM through an intricate network of transcription factors and miRNAs. I am also involved in the immunohistochemical evaluation of clinical trial samples based on my neuropathological expertise.

Education
PhD, Neuropathology, Kyushu University, Japan, 2010

MD, Nagasaki University, Japan, 2003

Awards
Brain Tumor Pathology Award, 2009

Genaro “Jerry”
Villa
Bio

Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults and, with a median survival of 15 months, among the most lethal of all cancers. GBM exhibits an altered metabolic program, including an increased dependence on cholesterol for cell growth, proliferation and survival. This dependence points to cholesterol regulation as a compelling therapeutic target in GBM. Our research focuses on pharmacologically targeting the cholesterol regulatory circuitry as an alternative therapeutic strategy for patients with this devastating disease.

Education
David Geffen School of Medicine at the University of California, Los Angeles, MD/PhD candidate, Medical Scientist Training Program, doctoral dissertation work in Mischel laboratory, 2007-present

BS, Molecular, Cell and Developmental Biology, University of California, Los Angeles, 2007

RESEARCH AREAS

Cancer is a genetic disease; it is also a biochemical one. Signal transduction networks and biochemical networks provide the interface between altered cancer genomes and the phenotypic hallmarks of cancer, thus providing a rich landscape of therapeutic targets. My laboratory aims to transform the care of patients with glioblastoma, the most common and lethal form of brain cancer in adults, through molecular medicine. We use quantitative molecular approaches to elucidate the signaling and biochemical networks that are altered in glioblastoma and develop strategies to target them. Our work integrates studies in cells, mice and patients in state-of-the-art molecularly guided clinical trials to develop more effective treatments. We have three main areas of research focus that are tightly interconnected:

• Targeting signal transduction pathways and identifying drug resistance mechanisms in glioblastoma

• Identifying the targetable metabolic circuitry activated by oncogenic signaling in glioblastoma

• Understanding the role of intratumoral heterogeneity in targeted cancer drug resistance

Click the links below to learn more.

Targeting signal transduction pathways and identifying drug resistance mechanisms in glioblastoma—the EGFR/PI3K/Akt/mTOR pathway

 

Targeting EGFR-activated Glioblastomas—identifying mechanisms of sensitivity and resistance

EGFR is the most common oncogene in glioblastoma, being amplified in 44% of clinical samples. Half of these tumors co-express a gain of function EGFR mutant, EGFRvIII, resulting from genomic deletion of exons 2-7. Work from Drs. Web Cavenee and Frank Furnari at Ludwig San Diego, our group, and others, demonstrates that EGFRvIII possesses potent ligand-independent oncogenic activity, promoting PI3K signaling, tumor growth and survival. Further EGFRvIII is required for glioblastoma maintenance. Thus, the failure of EGFR tyrosine kinase inhibitors in the clinic has been highly perplexing. This project is built on our observation that the loss of the PTEN tumor-suppressor protein, a negative regulator of PI3K signaling that is compromised in as much as 70% of glioblastomas, promotes resistance to EGFR tyrosine kinase inhibitors through maintained signal flux through the PI3K pathway (Mellinghoff et al, NEJM 2005). This observation was subsequently verified in other cancer types, and the finding that co-amplification of other receptor tyrosine kinase inhibitors can also promote EGFR inhibitor resistance has implicated a central role for maintained PI3K signal flux in driving EGFR tyrosine kinase inhibitor resistance. As a consequence, we are focusing on developing strategies to more effectively target EGFR/EGFRvIII and to target PI3K and its downstream effector mTOR in EGFR-activated glioblastomas. We have recently identified another novel mechanism of EGFR tyrosine kinase inhibitor resistance, mediated by transcriptional de-repression of PDGFRβ (Akhavan et al., Cancer Discovery 2013). A graphic summary of resistance mechanism is shown below.

 

Mischel figure 1, Ludwig Cancer Research

 

mTOR as a glioblastoma target

mTOR links upstream growth factor receptor signaling through PI3K with downstream protein translation and cellular proliferation. mTOR also integrates metabolic and growth factor signals in GBM, further highlighting its importance as a molecular target. We have demonstrated a critical role for mTOR signaling in glioblastoma pathogenesis and in mediating resistance to EGFR tyrosine kinase inhibitors (Cloughesy et al., PLoS Med., 2008) and identified mechanisms of mTOR inhibitor resistance including: 1) failure to suppress mTORC2 (Tanaka et al., Cancer Discovery 2011); and 2) upregulation of the promyelocytic leukemia protein (Iwanami et al., PNAS, 2013, Iwanami et al., Cell Cycle, 2013). Both of these resistance mechanisms are potentially pharmacologically targetable, forming the basis for future clinical trials. A schematic for the role of mTORC2 is shown below.

 

mTORC2 diagram, Paul Mischel, Ludwig Cancer Research

 

Future directions

We aim to identify targetable modifiers of drug response, including by uncovering synthetic lethal interactions. The overall goal is to develop more effective combination therapies and to test them in rigorously designed, molecularly based clinical trials.

 

Identifying the targetable metabolic circuitry activated by oncogenic signaling in glioblastoma

 

We made the surprising discovery that mutated EGFR promotes glioblastoma growth by driving lipogenesis, demonstrating a direct and targetable molecular link between an oncogene and an altered metabolic phenotype (Guo et al, PNAS, 2009;). Since then, we have dissected the molecular circuitry and identified the master transcriptional regulator of lipogenesis, SREBP-1, a gene whose importance in cardiovascular disease was well known, but whose importance in cancer was not appreciated, as the key link. Importantly, we have demonstrated that the lipogeneic phenotype is specifically, and potently, targetable in the clinic (Guo et al., Science Signaling, 2009). We have also made the surprising discovery that the EGFR oncogene promotes tumor growth and survival by up-regulating expression of the low-density lipoprotein receptor (LDLR) to bring massive amounts of cholesterol into the cell (Guo et al., Cancer Discovery 2011).

Since then, we have become interested in how EGFRvIII regulates glucose uptake and utilization to promote glioblastoma growth and survival. Alternative splicing contributes to diverse aspects of cancer pathogenesis, including altered cellular metabolism, but the specificity of the process or its consequences are not well understood. We recently characterized genome-wide alternative splicing induced by the activating EGFRvIII mutation in glioblastoma (GBM), identifying a novel mechanism by which EGFRvIII upregulates the heterogeneous nuclear ribonucleoprotein (hnRNP) A1 splicing factor, promoting glycolytic gene expression and conferring significantly shorter survival in patients. HnRNPA1 promotes splicing of a transcript encoding the Myc-interacting partner Max, generating Delta Max, an enhancer of Myc-dependent transformation. Delta Max, but not full-length Max, rescues Myc-dependent glycolytic gene expression upon induced EGFRvIII loss, and correlates with hnRNPA1 expression and downstream Myc-dependent gene transcription in patients. Finally, Delta Max is shown to promote glioma cell proliferation in vitro and augment EGFRvIII expressing GBM growth in vivo. These results demonstrate an important role for alternative splicing in GBM and identify Delta Max as a mediator of Myc-dependent tumor cell metabolism. (Babic et al., Cell Metabolism, 2013). A graphic scheme is shown below.

 

Delta Max, Paul S. Mischel, Ludwig Cancer Research

 

Future directions

We will focus on identifying the molecular circuitry by which EGFRvIII rewires glioblastoma metabolism, aiming to identify targetable nodes.

 

Understanding the role of intratumoral heterogeneity in targeted cancer drug resistance

 

Intratumoral cellular heterogeneity is a fundamental property of cancer. Its contribution to targeted drug resistance is poorly understood. Recent work from Drs. Cavenee and Furnari (Inda et al., Genes and Development 2010) demonstrates that intratumoral heterogeneity is actively maintained to promote glioblastoma growth and survival. To understand the impact of intratumoral cellular and molecular heterogeneity on glioblastome growth, survival and therapeutic resistance, new molecular diagnostic approaches to study signaling at the single cell level are needed to more effectively guide targeted therapies. In collaboration with Dr. Jim Heath at Cal Tech and Dr. Tim Cloughesy at UCLA, we are using novel micro- and nano-technologies to understand the population dynamics of cancer and its involvement in drug resistance (Wei et al., PNAS 2012; Wei et al, PNAS 2013).

 

Future directions

We aim to try to understand how intratumoral cellular and molecular heterogeneity contribute to the molecular evolution and treatment resistance of glioblastoma, and to use this information to develop more effective treatments. 

 

PUBLICATIONS

David A. Nathanson, Beatrice Gini, Jack Mottahedeh, Koppany Visnyei, Tomoyuki Koga, German Gomez1, Ascia Eskin, Kiwook Hwang, Jun Wang, Kenta Masui, Andres Paucar, Huijin Yang, Minori Ohashi, Shaojun Zhu, Jill Wykosky, Rachel Reed, Stanley F. Nelson, Timothy F. Cloughesy, C. David James, P. Nagesh Rao, Harley I. Kornblum, James R. Heath, Webster K. Cavenee, Frank B. Furnari, Paul S. Mischel. Targeted Therapy Resistance Mediated by Dynamic Regulation of Extrachromosomal Mutant EGFR DNA. Science. Published online December 5, 2013.

Masui K, Tanaka K, Akhavan D, Babic I, Gini B, Matsutani T, Iwanami A, Liu F, Villa GR, Gu Y, Campos C, Zhu S, Yang H, Yong WH, Cloughesy TF, Mellinghoff IK, Cavenee WK, Shaw RJ, Mischel PS. mTOR Complex 2 Controls Glycolytic Metabolism in Glioblastoma through FoxO Acetylation and Upregulation of c-Myc.

Cell Metab. 2013 Nov 5;18(5):726-39. doi: 10.1016/j.cmet.2013.09.013. Epub 2013 Oct 17.

Babic I, Anderson ES, Tanaka K, Guo D, Masui K, Li B, Zhu S, Gu Y, Villa GR, Akhavan D, Nathanson D, Gini B, Mareninov S, Li R, Camacho CE, Kurdistani SK, Eskin A, Nelson SF, Yong WH, Cavenee WK, Cloughesy TF, Christofk HR, Black DL, Mischel PS. EGFR Mutation-Induced Alternative Splicing of Max Contributes to Growth of Glycolytic Tumors in Brain Cancer. Cell Metab. 2013 May 22. doi:pii: S1550-4131(13)00156-3. 10.1016/j.cmet.2013.04.013. [Epub ahead of print]

Akhavan D, Pourzia AL, Nourian AA, Williams KJ, Nathanson D, Babic I, Villa GR, Tanaka K, Nael A, Yang H, Dang J, Vinters HV, Yong WH, Flagg M, Tamanoi F, Sasayama T, James CD, Kornblum HI, Cloughesy TF, Cavenee WK, Bensinger SJ, Mischel PS. De-Repression of PDGFRβ Transcription Promotes Acquired Resistance to EGFR Tyrosine Kinase Inhibitors in Glioblastoma Patients.
Cancer Discov. 2013 May;3(5):534-547. Epub 2013 Mar 26.

Iwanami A, Gini B, Zanca C, Matsutani T, Assuncao A, Nael A, Dang J, Yang H, Zhu S, Kohyama J, Kitabayashi I, Cavenee WK, Cloughesy TF, Furnari FB, Nakamura M, Toyama Y, Okano H, Mischel PS. PML mediates glioblastoma resistance to mammalian target of rapamycin (mTOR)-targeted therapies. Proc Natl Acad Sci U S A. 2013 Mar 12;110(11):4339-44. doi: 10.1073/pnas.1217602110. Epub 2013 Feb 25.

Tanaka K, Babic I, Nathanson D, Akhavan D, Guo D, Gini B, Dang J, Zhu S, Yang H, De Jesus J, Amzajerdi AN, Zhang Y, Dibble CC, Dan H, Rinkenbaugh A, Yong WH, Vinters HV, Gera JF, Cavenee WK, Cloughesy TF, Manning BD, Baldwin AS, Mischel PS. Oncogenic EGFR signaling activates an mTORC2-NF-κB pathway that promotes chemotherapy resistance. Cancer Discov. 2011 Nov;1(6):524-38. doi: 10.1158/2159-8290.CD-11-0124. Epub 2011 Sep 13.

LAB NOTES

LAB ALUMNI

Tomoo Matsutani, MD, PhD
2009-2012
Assistant Professor, Chiba University, Department of Neurosurgery, Chiba, Japan

Deliang Guo, PhD
2008–2012
Assistant Professor, Ohio State University, Department of Radiation Oncology

Akio Iwanami, MD, PhD
2009-2012
Assistant Professor, Keio University, Department of Orthopedic Surgery, Tokyo, Japan

Kazuhiro Tanaka, MD, PhD
2009-2012
Assistant Professor, Kobe University, Department of Neurological Surgery, Kobe, Japan

David Shackelford, PhD
2011-2012
(jointly with Reuben Shaw at the Salk Institute)
Assistant Professor, UCLA, Department of Molecular & Medical Pharmacology

David Nathanson, PhD
2008-2012
Post-doctoral fellow, UCLA, Department of Molecular and Medical Pharmacology

David Akhavan, PhD
2008-2012
Completing MD portion of MSTP program, UCLA

Alexandra Pourzia
2011-2012
MD, PhD Program, Harvard Medical School

Mary Youssef
2009-2011
MD, PhD Program, Columbia University

Felicia Reinitz
2008-2011
MD, PhD Program, Stanford University