Jeremy Rich Lab

Glioma Cancer Stem Cell and Brain Tumor

The mechanisms underlying tumor radioresistance remain elusive. We recently demonstrated that cancer stem cells contribute to glioma radioresistance through preferential activation of the DNA damage checkpoint response and increased DNA repair capacity (Nature, 2006).  The fraction of tumor cells expressing CD133 (prominin-1), a marker for both neural stem cells and brain cancer stem cells, was enriched after radiation in gliomas.  CD133+ glioma cells survive ionizing radiation at increased rates relative to the majority of tumor cells, which are CD133 negative.  CD133+ tumor cells preferentially activate the DNA damage checkpoint in response to radiation and repair radiation-induced DNA damage more effectively than CD133- tumor cells.  Furthermore, the radioresistance of CD133+ glioma stem cells can be reversed with a specific inhibitor of the Chk1/Chk2 checkpoint kinases.  These results suggest that CD133+ tumor cells represent the cellular population conferring glioma radioresistance and could be the source of tumor recurrence after radiation. Targeting DNA damage checkpoint response in cancer stem cells may overcome this radioresistance and provide a novel therapeutic paradigm for malignant brain cancers.

In additional studies, we examined the potential of CD133+ glioma cells to support tumor angiogenesis (Cancer Research, 2006). Tumors derived from CD133+ cells were morphologically distinguishable from CD133- tumor populations by widespread tumor angiogenesis, necrosis and hemorrhage.  In comparison to matched CD133- populations, CD133+ cells consistently secreted markedly elevated levels of vascular endothelial growth factor (VEGF), which were further induced by hypoxia. The pro-angiogenic effects of CD133+ glioma cells were specifically abolished by the anti-VEGF neutralizing antibody bevacizumab (Avastin), but bevacizumab had limited efficacy against matched CD133- populations.  Together these data indicate that stem cell-like tumor cells can be a crucial source of key angiogenic factors in cancers and that targeting pro-angiogenic factors from stem cell-like tumor populations may be critical for patient therapy.

Selected articles

1.        Shideng Bao, Qiulian Wu, Roger E. McLendon, Yueling Hao, Qing Shi, Anita B. Hjelmeland, Mark W. Dewhirst, Darell D. Bigner and Jeremy N. Rich.  Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 444, 756-760(7 December 2006) [PDF].

2.        Bao S, Wu Q, Sathornsumetee S, Hao Y, Li Z, Hjelmeland AB, Shi Q, McLendon RE, Bigner DD, and Rich JN. (2006) Stem cell-like glioblastoma cells promote tumor angiogenesis through vascular endothelial growth factor.  Cancer Res 66(16):7843-8 [PDF]

Transforming Growth Factor Beta Signaling

Dramatic therapeutic benefits of targeting specific signal transduction pathways in some cancers have pushed rational molecular targeting to the forefront of cutting-edge cancer therapy. The identification and targeting of pathways critical to the phenotype of cancers offers new hope in the treatment of many patients. Transforming growth factor (TGF-b) is a multifunctional polypeptide implicated in the regulation of a variety of cellular processes including growth, differentiation, apoptosis, adhesion, and motility. Abnormal activation or inhibition of these TGF-b regulated processes is implicated in many diseases, including multiple types of malignant brain tumors. TGF-b exerts a complex set of effects in cancers with an early tumor suppressive effect through growth inhibition but later effects in cancer development that are tumorigenic - including increased tumor cell motility and invasion, induction of angiogenesis, and immune suppression. Early preclinical and clinical studies have shown promise of anti-TGF-b strategies in the treatment of malignant gliomas suggesting TGF-b may be a potential new therapeutic target in neuro-oncology.

We are currently studying how specific components of the TGF-b pathway are altered in malignant glioma cell lines and transgenic glioma models to permit the resistance of these cells to the normal growth inhibition mediated by TGF-b. Additionally, we are interested how other signal transduction pathways that are commonly active in malignant gliomas interact with the TGF-b signal transduction pathway.

Selected articles

1.        Anita B. Hjelmeland, Mark D. Hjelmeland, Qing SHI, Janet L. Hart, Darell D. Bigner, Xiao-Fan Wang, Christopher D. Kontos and Jeremy N. Rich (2005), Loss of Phosphatase and Tensin Homologue Increases Transforming Growth Factor ß–Mediated Invasion with Enhanced SMAD3 Transcriptional Activity. Cancer Research; 65, 11276-11281, Dec. 15, 2005 [PDF]

2.        Rich JN, Zhang M, Datto MB, Bigner DD, Wang XF. Transforming growth factor-beta-mediated p15(INK4B) induction and growth inhibition in astrocytes is SMAD3-dependent and a pathway prominently altered in human glioma cell lines (1999). J Biol Chem 274(49): 35053-8, 1999 [PDF]

Secreted Protein Acidic and Rich in Cysteine (SPARC/Osteonectin)

The propensity for gliomas to invade normal tissues prevents surgical cures. Cancers frequently display alterations of the normal cell-matrix interactions linked to increased proliferation, invasion, and angiogenesis. One component of the ECM is osteonectin, also known as secreted protein, acidic and rich in cysteine (SPARC) or BM-40, which is a 43 KDa secreted extracellular glycoprotein that plays important roles in development, tissue healing and remodeling, and angiogenesis. Osteonectin was originally discovered as an important component of bone but is also expressed in epithelia exhibiting high rates of turnover. In addition to its normal physiological role, osteonectin has been linked to cancer progression as many cancer types express increased osteonectin expression upon invasion or metastasis. Gliomas do not metastasize but are highly invasive. Gliomas express osteonectin at sites of invasion and neoangiogenic blood-vessels at the brain-tumor interface. We have shown that malignant glioma cell lines engineered to overexpress osteonectin adopt an invasive phenotype both in vitro and in vivo associated with an increased expression of specific matrix metalloproteinases.

We are now studying the signaling pathways that mediate the effects of osteonectin in malignant glioma cell lines. Additionally, we are studying the contributions of osteonectin expression to glioma pathophysiology in transgenic glioma models. Finally, we have found cell type differences exist in the phenotype in the response to osteonectin. We are studying the mechanisms that account for these differences.

Selected Articles

1.        Qing SHI, Shideng Bao, Jill Maxwell, Elizabeth Reese, Darell D. Bigner, Xiao-Fan Wang, Jeremy N. Rich, Secreted Protein Acidic, Rich in Cysteine (SPARC) Mediates Cellular Survival of Glioma  through Akt Activity. J. Biol. Chem., 2004; 279: 52200-52209 [PDF]

2.        Jeremy N. Rich, Qing SHI, Mark Hjelmeland, Thomas J. Cummings, Chien-Tsun Kuan, Darell D. Bigner, Christopher M. Counter, and Xiao-Fan Wang, Bone-related Genes Expressed in Advanced Malignancies Induce Invasion and Metastasis in a Genetically Defined Human Cancer Model. J. Biol. Chem., 2003; 278: 15951-15957[PDF]

3.        Jeremy N. Rich, Christopher Hans, Beatrix Jones, Edwin S. Iversen, Roger E. McLendon, B.K. Ahmed Rasheed, Adrian Dobra, Holly K. Dressman, Darell D. Bigner, Joseph R. Nevins, and Mike West,  Gene Expression Profiling and Genetic Markers in Glioblastoma Survival. Cancer Res. 2005 65: 4051-4058 [PDF]

Preclinical Translational Studies

Traditional treatments rely on cytotoxic therapies that achieve effects through damage of DNA or disruption of the mitotic machinery. Novel therapies under development inhibit the activities of specific molecular targets that contribute to the malignancy of cancers. Current preclinical and clinical studies in neuro-oncology involve new therapeutic strategies that specifically target the unique molecular properties of gliomas. We are studying novel small molecule inhibitors of oncogenic pathways in preclinical glioma models. Current therapeutic targets include: epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), vascular endothelial growth factor receptor (VEGFR), TGF-b, mammalian target of rapamycin (mTOR), RAF kinase, AKT, and PI3K. Malignant gliomas are highly lethal tumors that display striking genetic heterogeneity. Novel therapies that inhibit a single molecular target may slow tumor progression, but tumors are likely not dependent on one signal transduction pathway. We, therefore, seek to determine predictors of tumor resistance or sensitivity to small molecule inhibitors of oncogenic pathways. In particular, we are interested on how two or more signal pathways interact such that combinations of small molecules may provide significantly improved efficacy over these agents as monotherapies.

Selected Articles

1.        Jeremy N. Rich, Darell D. Bigner, Development of novel targeted therapies in the treatment of malignant glioma. Nature Reviews Drug Discovery 3, 430-446 [PDF]

2.        Jeremy N. Rich, Sith Sathornsumetee, Stephen T. Keir, Mark W. Kieran, Andrea Laforme, Arja Kaipainen, Roger E. McLendon, Michael W. Graner, B.K. Ahmed Rasheed, Ling Wang, David A. Reardon, Anderson J. Ryan, Catherine Wheeler, Isaiah Dimery, Darell D. Bigner, and Henry S. Friedman. ZD6474, a Novel Tyrosine Kinase Inhibitor of Vascular Endothelial Growth Factor Receptor and Epidermal Growth Factor Receptor, Inhibits Tumor Growth of Multiple Nervous System Tumors. Clin. Cancer Res. 2005 11: 8145-8157 [PDF]

3.        Ranjit K. GOUDAR, Qing SHI, Mark D. Hjelmeland, Stephen T. Keir, Roger E. McLendon, Carol J. Wikstrand1, Elizabeth D. Reese, Francis Ali-Osman, Charles A. Conrad, Peter Traxler, Heidi A. Lane, David A. Reardon, Webster K. Cavenee, Xiao-Fan Wang, Darell D. Bigner, Henry S. Friedman, Jeremy N. Rich, Inhibition of receptor tyrosine kinases and mammalian target of rapamycin offers combinatorial benefit in tumor control. Molecular Cancer Therapeutics. 2005; 4: 101-112 [PDF]

4.        Mark D. Hjelmeland, Anita B. Hjelmeland, Sith Sathornsumetee, Elizabeth D. Reese, Michael H. Herbstreith, Nicholas J. Laping, Henry S. Friedman, Darell D. Bigner, Xiao-Fan Wang, and Jeremy N. Rich, SB-431542, a small molecule transforming growth factor-ß-receptor antagonist, inhibits human glioma cell line proliferation and motility. Mol. Cancer Ther. 2004 3: 737-745 [PDF]

5.        Sith Sathornsumetee, Anita B. Hjelmeland, Stephen T. Keir, Roger E. McLendon, David Batt, Timothy Ramsey, Naeem Yusuff, B.K. Ahmed Rasheed, Mark W. Kieran, Andrea Laforme, Darell D. Bigner, Henry S. Friedman, and Jeremy N. Rich (2006), AAL881, a Novel Small Molecule Inhibitor of RAF and Vascular Endothelial Growth Factor Receptor Activities, Blocks the Growth of Malignant Glioma. Cancer Res. 2006 66: 8722-8730 [PDF]

Clinical Translational Studies

Brain tumor patients are unique in their needs and challenges. Too often they have been told that there is no hope. My career objective is simple - give brain tumor patients hope not only in words but also in deed. While we do not expect to achieve instant victories in the near future, we are excited by the enticing capacity to now translate recent cancer biology advances into new treatment options. At the Brain Tumor Center at Duke we have created close partnerships between our internationally recognized brain tumor and cancer biology laboratories, the brain tumor clinic, and pharmaceutical companies. This partnership has already successfully brought new chemotherapies, immunotherapies, and small molecules into clinical trials. Critically, this discovery pipeline is not unidirectional. Rather, the seamless integration between the Brain Tumor Center, tissue bank, and brain tumor laboratories permits clinical data and tissue acquired in clinical trials to be used in an iterative process by which clinical efficacy of a therapy can guide future improvements. At no time has this process been as critical as therapies now directed towards specific molecular targets are under development. Several molecular targets are promising for glioblastomas, prominently the epidermal growth factor receptor (EGFR). Not only has the Duke Brain Tumor Center helped to define EGFR and its mutants as targets in glioblastomas under the leadership of Dr. Darell Bigner. We now are leading the evaluation of several anti-EGFR therapies for glioblastomas in clinical trials and laboratory studies. We now seek to advance the use of small molecule inhibitors for brain tumor patients through the following approaches:

Create a database of clinical data and tumor specimens from glioblastoma patients correlated with response to small molecules and molecular expression/activation. For example, we recently reported the first completed trial of Iressa (gefitinib) for glioblastoma patients. Lynch et al. and Paez et al. reported that mutations in the epidermal growth factor receptor (EGFR) kinase domain in lung cancers are associated with responsiveness to gefitinib. We recently performed a mutational analysis of the EGFR kinase region on tumor tissue from glioblastoma patients with an event-free survival of greater than 24 weeks in our phase II trial of gefitinib in glioblastoma patients. No mutations affecting the amino acid sequence in the kinase region were detected. We now seek alternative mechanisms by which glioblastoma sensitivity to EGFR inhibitors can be predicted.

Translate small molecule combinations into new clinical trials for glioblastoma patients. Future molecular approaches for glioblastomas will require targeting more than a single molecular target. We are currently launching clinical trials of small molecule combinations based on preliminary data from our preclinical investigations. We expect the rapid translation of additional advances in our understanding of glioblastoma dependence on specific signal transduction pathways into clinical trials with possibly improved outcomes.

We view these studies as a strong paradigm for a developmental program that will provide a firm foundation for the future translation of molecular therapies into the treatment of this lethal disease.

Selected Articles

1.        David A. Reardon, Jennifer A. Quinn, James J. Vredenburgh, Sridharan Gururangan, Allan H. Friedman, Annick Desjardins, Sith Sathornsumetee, James E. Herndon, II, Jeannette M. Dowell, Roger E. McLendon, James M. Provenzale, John H. Sampson, Robert P. Smith, Alan J. Swaisland, Judith S. Ochs, Peggy Lyons, Sandy Tourt-Uhlig, Darell D. Bigner, Henry S. Friedman, and Jeremy N. Rich, Phase 1 Trial of Gefitinib Plus Sirolimus in Adults with Recurrent Malignant Glioma. Clin. Cancer Res. 2006 12: 860-868 [PDF]

Current Laboratory Members

Jeremy Rich, Principal Investigator

Shideng Bao, Assistant Research Professor

 Brian Fee, Research Analyst I

Wen-chi Foo, Medical Student

Yueling Hao, Research Technician II

Anita Hjelmeland, Assistant Research Professor

Pei Miao, Research Technician I

Sith Sathornsumetee, Neurology Fellow

Qing Shi, Research Analyst II

Linhua Song, Research Analyst I

Yue Hua Sun, Research Analyst I

Sarah Wickman, Research Technician II

Qiulian Wu, Research Analyst II

Yiting Cao, Post-doctoral Fellow

Christy Eyler, Rotation Graduate Student

Katie Lattimore, Undergraduate

Jennifer Elderbroom, Rotation Graduate Student

Zhizhong Li, Graduate Student

Alias Prager, Undergraduate

Grant Support

None of our studies would be possible without the generous support of several funding agencies and foundations. The laboratory is supported in part by funds from the Pediatric Brain Tumor Foundation of the United States, Accelerate Brain Cancer Cure, Childhood Brain Tumor Foundation, Southeastern Brain Tumor Foundation, and the Duke Comprehensive Cancer Center Stem Cell Initiative. This work was also supported by NIH grants NS047409, NS054276, and CA116659.  Dr. Hjelmeland is a Paul Brazen/American Brain Tumor Association Fellow.  Dr. Rich is a Damon Runyon-Lilly Clinical Investigator supported by the Damon Runyon Cancer Research Foundation and a Sidney Kimmel Foundation for Cancer Research Scholar.