Mechanisms of drug action and resistance with the goal of improving therapeutic outcomes for cancer patients.
My group has focused on mechanisms of drug action and resistance with the goal of developing predictive tests that improve therapeutic outcomes for cancer patients. Active areas in my laboratory at UC Irvine include the role of glutathione and redox mechanisms in drug resistance, development of vascular endothelial cell models to predict response to antiangiogenesis agents, and the examination of differential gene expression that can distinguish between drug resistant and drug sensitive tumors. Recently we have focused on translating our bench work to the bedside through the development of clinical trials that include correlative laboratory studies.
Discovery of agents that inhibit formation of tumor blood vessels is an active area of therapeutic development. Angiogenesis is an attractive target because endothelial cell response to the tumor microenvironment involves the same stable pathways invoked in wound healing. In contrast, tumor signaling pathways are constantly mutating, and so present a moving therapeutic target compared to the more stable endothelial cell pathways. It may therefore be easier to inhibit angiogenesis with agents that selectively target pathways unique to activated vascular endothelial cells, thereby starving tumors, than to kill tumors directly with less specific chemotherapeutic agents. However, resistance to antiangiogenesis agents as a deterrent to the success of this approach has been overlooked. In order to define the role of angiogenesis in tumor progression, and to develop models that might predict treatment response, my group developed an angiogenesis index based on mutant p53, the angiogenesis suppressor thrombospondin-1 (TSP1), and intratumor microvessel counts (US Patent # 5,840,507). Funded in part by the California Cancer Research Program, we found that these biomarkers predicted disease progression in melanoma and ovarian cancer and survival in prostate cancer (Cancer Det and Prev 22(3): 185, 1998; Gyn Oncol 78:130, 2000; Clin Cancer Res 7:81, 2001). My lab is now integrating these biomarkers into clinical trials for patients with breast cancer, ovarian cancer, cervical cancer and melanoma. One hurdle for such trials relates to the weakness of conventional imaging modalities to measure treatment response to antiangiogenesis agents. Our group, in collaboration with Dr. Orhan Nalcioglu in the departments of physics and radiology at UC Irvine, is studying patients on an NCI funded clinical study to determine if our biomarker index, in conjunction with dynamic contrast enhanced magnetic resonance imaging, can predict clinical response to this novel class of agents. Preliminary data suggest that our methods may provide an effective means to determine changes in intratumor blood flow during anitangiogenesis therapy (Technol Cancer Res Treat 1(6): 479, 2002).
Recently, our group has explored the relationship between tumor class, drug response and differential gene and protein expression (Clinical Cancer Res 5 (Suppl), #476, 1999). One significant deficiency in current molecular approaches to cancer genomics is specimen purity. The complex mixture of cells within a tumor makes it difficult to delineate which mRNA species are cancer cell specific. We therefore developed flow-cytometry methods to selectively separate malignant cells and tumor derived vascular endothelial cells (VEC) from their stromal background tissue. Transcript levels were determined for the purified cancer cell and VEC cell populations using Affymetrix U133 A and B gene arrays containing 30,000 distinct genes and EST’s. Differential gene expression patterns that classify endothelial cells into drug resistance categories have been identified (Proc Am Assoc Cancer Res 43: #4502, 2002; Breast Cancer Res and Treat 76: #562, 2002; Proc Am Assoc Cancer Res 2003, #3998 (Minisymposium Podium Presentation).
My current position as Director of Clinical Pharmacology and Developmental Therapeutics in the Chao Family Comprehensive Cancer Center at UC Irvine allows me to take a translational approach to predictive oncology and to apply bioprofiling to patients on clinical trials. The tremendous complexity of aberrant pathways in cancer has been a major deterrent in the development of targeted therapeutics. With the advent of gene arrays and advanced mass spectrometry methods, this complexity may finally be captured. The capability to bioprofile the unique proteogenomic characteristics of an individual patient’s tumor is at hand. Co-development of proteogenomic “theragnostic” tests in conjunction with clinical trials of targeted agents should define those patient subsets most likely to benefit, while excluding patients with inappropriate biomarker profiles from potentially toxic treatment. The convergence of biotechnology, molecular biology and clinical pharmacology with bioinformatics should enable a rational approach to target cancer related pathways and improve outcomes for patients with cancer. Application of these new techniques will not be limited to Oncology, but will be used in all medical specialties to further improve healthy outcomes for our patients.
Our angiogenesis model has been extended to include three dimensional cancer cell line spheroids into which vascular endothelial cells migrate. We are currently examining the effects of sunitinib and axitnib, two agents that inhibit VEGF-receptor tyrosine kinase activity to validate the vascularized spheroid model.
The tremendous complexity of aberrant pathways in cancer has been a major deterrent in the development of targeted therapeutics. With the advent of gene arrays and advanced mass spectrometry methods, this complexity may finally be captured. The capability to bioprofile the unique proteogenomic characteristics of an individual patient’s tumor is at hand. Co-development of proteogenomic “theragnostic” tests in conjunction with clinical trials of targeted agents should define those patient subsets most likely to benefit, while excluding patients with inappropriate biomarker profiles from potentially toxic treatment. The convergence of biotechnology, molecular biology and clinical pharmacology with bioinformatics should enable a rational approach to target cancer related pathways and improve outcomes for patients with cancer.
Parker R. Mehta R, Filka E, Fruehauf JP, Cloughesy T. A prospective blinded study of the predictive value of extreme drug resistance assays in patients receiving CPT-11 for recurrent glioma. J Neuro-Oncology, 66:365-375, 2004.
Fruehauf JP, Kong KM, Jakowatz JG. Docetaxel and vinorelbine plus GM-CSF in malignant melanoma. Oncology 19 (suppl 2):19-22, 2005.
Goodhart M, Fruehauf JP, Buller R. The Relationship Of Molecular Markers Of P53 Function And Angiogenesis To Prognosis Of Stage I Epithelial Ovarian Cancer. Clin Cancer Res 11:3733-3742, 2005.
Tewari K, Mehta RS, Burger RA, Yu I-R, Kyshtoobayeva AS, Monk BJ, Manetta A, Berman ML, DiSaia PJ, Fruehauf JP. Conservation of in vitro drug resistance profiles in epithelial ovarian cancer. Gynecol Oncol 98:360-368, 2005.
Tewari D, Monk BJ, Parker R, Heck JD, Burger RA, Fruehauf JP. Gene expression profiling of in vitro radiation resistance in cervical carcinoma: a feasibility study. Gynecol Oncol 99(1):84-91, 2005.
Fruehauf JP, Brem H, Brem S, Sloan A, Barger G, Parker R. In Vitro Drug Response and Molecular Markers Associated with Drug Resistance in Malignant Gliomas. Clin Can Res 12:4523-32, 2006
Prabhu S, Saadat D, Zhang M, Halbur L, Fruehauf JP, Ong ST. A novel mechanism for Bcr-Abl action: Bcr-Abl-mediated induction of the eIF4F translation initiation complex and mRNA translation. Oncogene 26:1188-200, 2007.
Nishimoto KP, Newkirk D, Hou S, Fruehauf J, Nelson EL. Fluorescence activated cell sorting (FACS) using RNAlater to minimize RNA degradation and perturbation of mRNA expression from cells involved in initial host microbe interactions. J Microbiol Methods. 70(1):205-8, 2007.
Einspahr JG, Thomas TL, Saboda K, Nickolof BJ, Wameke J, Curiel-Lewandrowski C, Ranger-Moore J, Duckett L, Bangert J, Fruehauf JP, Alberts DS. Expression of VEGF in early cutaneous melanocytic lesion progression. Cancer: Oct 11, 2007 epub
Mathews MS, Linskey ME, Hasso A, Fruehauf JP. The effect of bevacizumab (Avastin) on neuroimaging of brain metastases. Surgical Neurology 2007. In press
Su M-Y, Yu H, Chiou J-Y, Wang J, Fruehauf JP, Nalcioglu O, Mehta RS, Baick CH. Measurements of Volumetric Changes and Vascular Changes with Dynamic Contrast Enhanced MRI for Cancer Therapy Monitoring. Technology in Cancer Research and Treatment, 1(6): 479-488, 2002
Park SW, Lomri N, Simeoni LA, Fruehauf JP, Mechetner E. Analysis of p-glycoprotein mediated membrane transport in human peripheral blood lymphocytes using the UCI2 shift assay. Cytometry 53A:67-78, 2003
PI, HDII Clinical Trial UCI 09-53 Phase II Pazopanib plus Docetaxel for Stage IV Melanoma. $500,000
American Association for Cancer Research
American Society of Clinical Oncology
SWOG, Breast and Melanoma Committees
Medical Oncology Association of Southern California (MOASC)
Co-Director, Melanoma Translational Working Group
Director, Clinical Pharmacology and Developmental Therapeutics
Chao Family Comprehensive Cancer Center