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.
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
Fruehauf JP, Kong K, Jakowatz JG. Phase II clinical trial evaluating docetaxel and vinorelbine plus GM-CSF in malignant melanoma. Oncology 19 (suppl 2):19-22, 2005.
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
Fruehauf JP, Brem H, Brem S, Sloan A, Barger G, Huang W, Parker R. In vitro drug response and molecular markers associated with drug resistance in malignant gliomas. Clin Can Res 12:4523-32, 2006. (86)
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. (58)
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 Vascular Endothelial Growth Factor in early cutaneous melanocytic lesion progression. Cancer: 110:2519-27, 2007. (64)
Mathews MS, Linskey ME, Hasso AN, Fruehauf JP. The effect of bevacizumab (Avastin) on neuroimaging of brain metastases. Surg Neurol. 70(6):649-53, 2008. (41)
Zhang M, Fu W, Prabhu S, Moore JC, Ko J, Kim JW, Druker BJ, Trapp V, Fruehauf J, Gram H, Fan HY, Ong ST. Inhibition of polysome assembly enhances imatinib activity against chronic myelogenous leukemia, and overcomes imatinib resistance. Mol Cell Biol 28:6496-509, 2008. (67)
Finley DS, Narula N, Valera VA, Merino MJ, Fruehauf J, Wu ML, Linehan WM, Clayman RV. Immunohistochemical basis for adjuvant anti-angiogenic targeted therapy for renal carcinoid: Initial case report. Urol Oncol 2008 Dec 24. [Epub ahead of print; paper publication 29:85-89, 2011 (9)
Frieboes HB, Edgerton ME, Fruehauf JP, Rose FRAJ, Worrall LK, Gatenby RA, Ferrari M, Cristini V. Prediction of drug response in breast cancer using integrative experimental/computational modeling. Cancer Res 69(10):4484-92, 2009. (141)
Trapp V, Lee K, Doñate F, Mazar AP, Fruehauf, JP. Redox-related antimelanoma activity of ATN-224. Melanoma Research 19(6):350-360, 2009. (7)
46. Randall LM, Monk BJ, Darcy KM, Tian C, Burger RA, Liao S-Y, Peters WA, Stock RJ, Fruehauf JP. Markers of angiogenesis in high-risk, early-stage cervical cancer: A Gynecologic Oncology Group study. Gynecologic Oncology, 112(3):583-9, 2009. (113)
Liao SY, Darcy KM, Randall LM, Tian C, Monk BJ, Burger RA, Fruehauf JP, Peters WA, Stock RJ, Stanbridge EJ. Prognostic relevance of carbonic anhydrase-IX in high-risk, early-stage cervical cancer: A Gynecologic Oncology Group study. Gynecol Oncol. 116(3):452-8, 2010. (64)
Tran Cao HS, Bouvet M, Kaushal S, Keleman A, Romney E, Kim G, Fruehauf J, Imagawa DK, Hoffman RM, Katz MH. Metronomic gemcitabine in combination with sunitinib inhibits multisite metastasis and increases survival in an orthotopic model of pancreatic cancer. Mol Cancer Ther 9:2068-78, 2010. (51)
Trapp V, Parmakhtiar B, Papazian V, Willmott L, Fruehauf JP. Anti-angiogenic effects of resveratrol mediated by decreased VEGF and increased TSP1expression in melanoma-endothelial cell co-culture. Angiogenesis 13:305-15, 2010. (110)
Han ES, Burger RA, Darcy KM, Sill MW, Randall LM, Chase D, Parmakhtiar B, Monk BJ, Greer BE, DeGeest K Fruehauf JP. Predictive and prognostic angiogenic markers in a Gynecologic Oncology Group Phase II Trial of Bevacizumab in recurrent and persistent ovarian or peritoneal cancer. Gynecol Oncol 119(3):484-90, 2010. (62)
Randall LM, Monk BJ, Moon J, Parker R, Al-Ghazi M, Wilczynski S, Fruehauf JP, Markman M, Burger RA. Prospective evaluation of an in vitro radiation resistance assay in locally advanced cancer of the uterine cervix: a Southwest Oncology Group Study. Gynecol Oncol 119:417-21, 2010. (10)
Tang Y, Parmakhtiar B, Simoneau AR, Xie J, Fruehauf J, Lilly M, Zi X. Lycopene enhances docetaxel's effect in castration-resistant prostate cancer associated with insulin-like growth factor I receptor levels. Neoplasia. 13:108-19, 2011. (101)
Rini BI, Schiller JH, Fruehauf JP, Cohen EEW, Tarazi JC, Rosbrook B, Bair AH, Ricart AD, Olszanski AJ, Letrent KJ, Kim S, Rixe O. Diastolic blood pressure as a biomarker of axitinib efficacy in solid tumors. Clin Cancer Res 17:3841-9, 2011. (194)
Eroglu Z, Kong KM, Jakowatz JG, Samlowski W, Fruehauf JP. Phase II clinical trial evaluating docetaxel, vinorelbine and GM-CSF in stage IV melanoma. Cancer Chemother Pharmacol. 68:1081-7, 2011. (14)
Fruehauf JP, Lutzky J, McDermott DF, Brown CK, Meric J-B , Rosbrook B, Shalinsky DR, Liau KF, Niethammer AG, Kim S, Rixe O. Multicenter, phase II study of axitinib, a selective second-generation inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, in patients with metastatic melanoma. Clin Cancer Research. 17:7462-7469, 2011. (105)
Kim KB, Sosman JA, Fruehauf JP, Linette GP, Markovic SN, McDermott DF, Weber JS, Nguyen H, Cheverton P, Chen D, Peterson AC, Carson WE 3rd, O'Day SJ. BEAM: A Randomized Phase II Study Evaluating the Activity of Bevacizumab in Combination with Carboplatin Plus Paclitaxel in Patients with Previously Untreated Advanced Melanoma. J Clin Oncol. 30:34-41, 2012. (175)
Chase DM, Sill MW, Monk BJ, Chambers MD, Darcy KM, Han ES, Buening BJ, Sorosky JI, Fruehauf JP, Burger RA. Changes in Tumor Blood Flow as Measured by Dynamic Contrast-Enhanced Magnetic Resonance Imaging (DCE-MRI) May Predict Activity of Single Agent Bevacizumab in Recurrent Epithelial Ovarian (EOC) and Primary Peritoneal Cancer (PPC) Patients: An exploratory analysis of a Gynecologic Oncology Group Phase II study. Gynecol Oncol 126:375-80, 2012. (20)
van der Graaf WT, Blay JY, Chawla SP, Kim DW, Bui-Nguyen B, Casali PG, Schöffski P, Aglietta M, Staddon AP, Beppu Y, Le Cesne A, Gelderblom H, Judson IR, Araki N, Ouali M, Marreaud S, Hodge R, Dewji MR, Coens C, Demetri GD, Fletcher CD, Dei Tos AP, Hohenberger P; EORTC Soft Tissue and Bone Sarcoma Group; PALETTE study group. Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomized, double-blind, placebo-controlled phase 3 trial. Lancet 379:1879-86, 2012. (1323)
Lindner DJ, Wu Y, Haney R, Jacobs BS, Fruehauf JP, Tuthill R, Borden EC. Thrombospondin-1 expression in melanoma is blocked by methylation and targeted reversal by 5-Aza-deoxycytidine suppresses angiogenesis. Matrix Biol. 32:123-132, 2013. (49)
Eroglu Z, Fruehauf JP. A phase II study of gemcitabine and oxaliplatin in advanced transitional cell carcinoma of the bladder. Cancer Chemother Pharm 72: 263-267, 2013. (10)
Tortorici MA, Cohen EE, Pithavala YK, Garrett M, Ruiz-Garcia A, Kim S, Fruehauf JP. Pharmacokinetics of single-agent axitinib across multiple solid tumor types. Cancer Chemother Pharmacol. 74(6):1279-89, 2014. (7)
Saad F, Fizazi K, Jinga V, Efstathiou E, Fong PC, Hart LL, Jones R, McDermott R, Wirth M, Suzuki K, MacLean DB, Wang L, Akaza H, Nelson J, Scher HI, Dreicer R, Webb IJ, de Wit R; ELM-PC 4 investigators. Orteronel plus prednisone in patients with chemotherapy-naive metastatic castration-resistant prostate cancer (ELM-PC 4): a double-blind, multicenter, phase 3, randomized, placebo-controlled trial. Lancet Oncol 16:338-48, 2015. (68)
Fruehauf JP, El-Masry M, Osann K, Parmakhtiar B, Yamamoto M, Jakowatz JG. Phase II study of pazopanib in combination with paclitaxel in patients with metastatic melanoma. Cancer Chemother Pharmacol 82:353–360, 2018. (8)
Liau MC, Kim J-H, Fruehauf JP. Potentiation of ATRA activity in HL-60 cells by targeting methylation enzymes. J Pharmacol Pharmaceut Pharmacovig 3:009, 2019.
Rini BI, Plimack ER, Stus V, Gafanov R, Hawkins R, Nosov D, Pouliot F, Alekseev B, Soulières D, Melichar B, Vynnychenko I, Kryzhanivska A, Bondarenko I, Azevedo SJ, Borchiellini D, Szczylik C, Markus M, McDermott RS, Bedke J, Tartas S, Chang YH, Tamada S, Shou Q, Perini RF, Chen M, Atkins MB, Powles T; KEYNOTE-426 Investigators. Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med. 380:1116-1127, 2019. (493)
Schmidinger M, Bamias A, Procopio G, Hawkins R, Sanchez AR, Vázquez S, Srihari N, Kalofonos H, Bono P, Pisal CB, Hirschberg Y, Dezzani L, Ahmad Q, Jonasch E; PRINCIPAL Study Group. Prospective Observational Study of Pazopanib in Patients with Advanced Renal Cell Carcinoma (PRINCIPAL Study). Oncologist 24:491-4907, 2019. (7)
Parmakhtiar B, Burger RA, Kim J-H, Fruehauf JP. HIF inactivation of p53 in ovarian cancer can be reversed by topotecan restoring cisplatin and paclitaxel sensitivity. Molecular Cancer Res. 17:1675-1686, 2019. (18)
Liau MC, Kim J-H, Fruehauf JP. Potentiation of ATRA activity in HL-60 cells by targeting methylation enzymes. J Pharmacol Pharmaceut Pharmacovig 3: 009, 2019. (3)
Liau MC, Fruehauf PA, Zheng Z-H, Fruehauf JP. Development of Synthetic Cell Differentiation Agent Formulations for the Prevention and Therapy of Cancer via Targeting of Cancer Stem Cells. Cancer Stud Ther J 4(1): 1–15, 2019. (4)
Liau MC, Kim JH, Fruehauf JP. In Pursuance of Differentiation Inducers to Combat Cancer via Targeting of Abnormal Methylation Enzymes. J Cancer and Tumor Int. 10: 39-47, 2020. (2)
Liau MC, Kim JH, Fruehauf JP. Arachidonic acid and its metabolites as surveillance differentiation inducers to protect healthy people from becoming cancer patients. ClinPharmacolToxicol Res, 2021 - m.ztcbaoan.com (3)
Zhuang E, Jakowatz JG, Yamamato M and Fruehauf JP An Open Label, Phase II Study of Neoadjuvant Axitinib in Patients with Stage III Malignant Melanoma. Res Rev Hema Oncol. 2021; 1:102.
Fruehauf JP, Zhuang E, Uchio E, Lilly M, Zi X, A phase II study of docetaxel plus lycopene in metastatic castrate resistant prostate. Biomedicine & Pharmacotherapy. 2021. In press.
PI, HDII Clinical Trial UCI 09-53 Phase II Pazopanib plus Docetaxel for Stage IV Melanoma. $500,000
Industry Sponsored Trial/ UCI-18-64 : RPL-001-16 An Open-Label, Multicenter, Phase 1/2 Study of RP1 as a Single Agent and in Combination with PD1 Blockade in Patients with Solid Tumors.
Industry Sponsored Trial/ UCI-20-57: A Phase 3, Randomized, Open-label Study to Compare Adjuvant Immunotherapy of Bempegaldesleukin Combined with Nivolumab Versus Nivolumab After Complete Resection of Melanoma in Patients at High Risk for Recurrence (PIVOT-12).
PI $593,944 (T) 11/01/2020 - 10/31/2023
Industry Sponsored Trial/ UCI-19-140: A Randomized Phase II, Open-label, Active-controlled, Multicenter Study Investigating the Efficacy and Safety of UV1 Vaccination in Combination with Nivolumab and Ipilimumab as First-line Treatment of Patients with Unresectable or Metastatic Melanoma (UV1-202).
PI $338,316 (T) 09/01/2020 - 08/31/2023
Industry Sponsored Trial/ UCI-20-116: A RANDOMIZED, CONTROLLED, OPEN-LABEL, PHASE 2 STUDY OF CEMIPLIMAB AS A SINGLE AGENT AND IN COMBINATION WITH RP1 IN PATIENTS WITH ADVANCED CUTANEOUS SQUAMOUS CELL CARCINOMA.
PI $493,338 (T) 11/01/2020 - 10/31/2023
Industry Sponsored Trial/ UCI-19-15 A Phase 2, Open-Label, Randomized, Multicenter Trial of Encorafenib + Binimetinib Evaluating a Standard-dose and a High-dose Regimen in Patients With BRAFV600-Mutant Melanoma Brain Metastasis
PI $299,658 (T) 11/5/19-10/21/22
Industry Sponsored Trial/ UCI-17-73: A Sequential 2-arm, Open-label Phase 1 Study to Evaluate the Effects of Encorafenib in Combination with Binimetinib on the Pharmacokinetics of Losartan, Midazolam, Caffeine, Omeprazole, and Dextromethorphan Administered in a Cocktail Approach and on the Pharmacokinetics of Rosuvastatin in Patients with BRAF V600-mutant Unresectable or Metastatic Melanoma or Other Advanced Solid Tumors.
PI $171,895.00 (T) 1/24/18 – 10/21/22
Industry Sponsored Trial/ UCI-16-102: A PHASE III, OPEN-LABEL, MULTICENTER, TWO-ARM, RANDOMIZED STUDY TO INVESTIGATE THE EFFICACY AND SAFETY OF COBIMETINIB PLUS ATEZOLIZUMAB VERSUS PEMBROLIZUMAB IN PATIENTS WITH PREVIOUSLY UNTREATED ADVANCED BRAFV600 WILD-TYPE MELANOMA
PI $378,399.00 (T). 11/15/17 - 11/14/20
Industry Sponsored Trial/ UCI 17-09: A randomized, double-blind, placebo-controlled, phase III study comparing the combination of PDR001, dabrafenib and trametinib versus placebo, dabrafenib and trametinib in previously untreated patients with unresectable or metastatic BRAF V600 mutant melanoma
PI $507,335.00 (T). 08/01/17 - 07/31/20
Industry Sponsored Trial / UCI-16-92: A Phase III, Double-Blinded, Randomized, Placebo-Controlled Study of Atezolizumab Plus Cobimetinib and Vemurafenib versus Placebo plus Cobimetinib and Vemurafenib in Previously Untreated BRAFV600 Mutation-Positive Patients with Unresectable Locally Advanced or Metastatic Melanoma
PI $689,151.00 (T). 2/15/17 - 5/30/22
Industry Sponsored Trial / UCI 16-63
Phase III Randomized, Open-label Study to Evaluate Efficacy and Safety of Pembrolizumab (MK-3475
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