In its scientific agenda, the Division is increasing its emphasis on translational research based on fundamental concepts of molecular biology. This approach has been predicated on the emerging knowledge of the molecular correlates of anticancer drug resistance, increased understanding of the genes associated with familial and sporadic patterns of malignancy (colorectal and breast cancer, in particular), the immunological basis of tumor response and resistance, and a more precise assessment of the pharmacology of novel anticancer compounds. In this way, the Division has become even more central to the translational research program of the USC/Norris Comprehensive Cancer Center.

The Division has increased its interaction with scientists of the USC/Norris Comprehensive Cancer Center , which has led to several interdisciplinary projects that have allowed overlap of several of the scientific programs of the center—Genitourinary, Gastrointestinal, Breast Cancer, Developmental Therapeutics and several core programs. Our list of publications attests to the level of interdisciplinary collaboration that has been achieved, including: detailed reports of preclinical assessment of new anticancer compounds, pharmacology of anticancer agents, molecular mechanisms of resistance to fluoropyrimidine and other cytotoxic agents, and genes associated with breast, genitourinary and colon cancer. Members of the Division have also assumed a leadership role in a key NIH-funded multi-center trial assessing molecular correlates and utility of adjuvant chemotherapy for invasive bladder cancer.

Members of the Division have assumed leadership roles in the scientific agenda of the Southwest Oncology Group, with emphasis on cancers of the genitourinary tract, breast, gastrointestinal tract, bronchus and skin, and have provided core laboratory resources for translational trials conducted by the Southwest Oncology Group and the Cancer. Important clinical and scientific leadership has been provided to the Phase I-II Consortium (funded by the National Cancer Institute and shared between City of Hope National Medical Center, University of California-Davis and USC). Extension of this work in the Division Cancer Medicine and Blood Diseases has led to an important collaboration with the staff of Children’s Hospital of Los Angeles in the development of several novel anticancer agents, with an emphasis on retinoid biology in cancer therapeutics.

Members of the Division have led the USC program of immunotherapeutic research in cancer, with the development of tumor antibodies as therapeutic tools, and the use of novel cytokines administered by inhalational routes. Of particular importance has been the study of vaccines for patients with malignant melanoma and with cervical cancer, as well as the utility of bispecific antibodies directed against determinants on prostate cancer.

Faculty Research Areas

John R. Daniels, M.D.
Chemoembolization of Liver Tumors
Breast Cancer Prevention

Tanya Dorff, M.D.
Treatment of Genitourinary Malignancies
Molecular/genetic markers of response to chemotherapy and hormone therapy in prostate cancer
Testosterone therapy in prostate cancer
Perioperative chemotherapy in bladder cancer
Early prostate cancer – HGPIN predictors of progression, imaging and active surveillance

Anthony El-Khoueiry, M.D.
Development of Phase I Program for Drug Development in GI Oncology
Design and Conduct of Clinical Trial in GI Oncology

Barbara J. Gitlitz, M.D.
In vivo Generated Dendritic Cell Based Immunotherapy
Treatment of Lung Cancer
Clinical Trials in Head and Neck Cancer

Helen Gu, M.D.
Neuro-oncological cancers

Amir Goldkorn, M.D.
Treatment of Genitourinary Malignancies
Investigation of Novel Therapies Targeting Telomerase and Cancer Stem Cells

Syma Iqbal, M.D.
Esophageal Cancer
Gastric Carcinoma
Metastatic Gallbladder and Colon Cancers

James Hu, M.D.
Sarcoma
Testicular cancers

Heinz-Josef Lenz, M.D.
Molecular Tumor Profiling to Predict Outcome
Regulation of Gene Expression Involved in Drug Resistance (TS, TP, ERCC1, GST-P1, XPD)
Germline Polymorphisms as Predictors of Clinical Outcome and Toxicity
Development of Novel Agents and Identification of Novel Targets

Jacek K. Pinski, M.D., Ph.D.
Prostate Cancer
Clinical Trials in Hormone Refractory Prostate Cancer

David I. Quinn, M.D., Ph.D.
Clinical and Molecular Predictors of Cancer Outcome
Molecular Cancer Profiling for New Therapeutic Targets
Development of New Anticancer Therapies – Phase I/II Trials and Molecular Correlates

Christy A. Russell, M.D.
Prevention and Systemic Treatment of Breast Cancer

Darcy V. Spicer, M.D.
Breast Cancer Treatment and Prevention
Human Subjects Research

Debu Tripathy, M.D.
Treatment of Breast Cancer
Evaluation of Novel Anti-cancer Agents and other Clinical Trials for Breast Cancer

Special Basic Research Activities

Amir Goldkorn, M.D.
My lab’s goal is to develop novel therapies targeting cancers of the genitourinary (GU) tract. We conduct basic and translational research in the field of experimental therapeutics, focusing on telomerase interference, targeted gene delivery, and cancer stem cell targeting. Specifically, we have found that introduction of mutated telomerase RNA into cancer cells elicits a rapid apoptotic response and inhibits proliferation across all cancer types, independent of telomere shortening. We are studying the apoptotic mechanisms underlying this dramatic phenomenon, and we are testing its therapeutic potential, alone and in combination with existing therapies, in prostate, kidney and bladder cancers. For systemic in vivo delivery, we have transitioned telomerase interference into a mouse prostate cancer model and are collaborating to develop effective tumor-specific targeted delivery. Another research focus is on telomerase and cancer stem cells. Recent findings suggest that cancer metastases and recurrences may be mediated by a unique sub-population of tumor cells, dubbed cancer stem cells, which possess the capacity to self-renew and to differentiate into additional tumors while remaining unscathed by available treatments. A significant body of evidence has emerged demonstrating a critical role for telomerase in stem cell activation. We are isolating and characterizing cancer stem cells from tumor tissues acquired from mouse models and from patient samples, and we are investigating whether telomerase interference can effectively neutralize these cells. In summary, by studying telomerase-induced apoptosis, by optimizing targeted delivery, and by specifically impacting cancer stem cell populations, we ultimately hope to improve treatment options for metastatic and recurrent cancers.

Jacek K. Pinski, M.D., Ph.D.
Dr Pinski’s laboratory studies the role of novel molecular prognostic markers in patients with prostate cancer. Such serum and tissue markers might not only help to better evaluate clinical outcomes of patients but they could also lead to more effective therapies.
Another area of research in Dr Pinski’s laboratory is the role and significance of neuroendocrine differentiation in normal and malignant prostate. A better understanding of this phenomenon could also result in improved therapies for patients with prostate cancer.
In addition, novel experimental anti-cancer compounds, like an anti-IL-6 antibody, the disintegrin contortrostatin and an LH-RH analog linked to a cytotoxic agent, are being investigated in Dr Pinski’s laboratory for efficacy against prostate cancer and better understanding of their mechanisms of action.

Debu Tripathy, M.D.

Our laboratory and translational studies are aimed at defining new targets for breast cancer therapy, particularly those involved in growth factor receptors function and signal transduction.  We utilize preclinical models as well as human tumor specimens to elucidate mechanisms of resistance and responsiveness as well as evolutionary changes such as bypass mechanisms that arise upon exposure to therapy and other selective pressures.  Chemokine receptors and ligands appear to play a role in metastases and drug resistance.  In our models, the chemokine receptor CXCR4 is upregulated in trastuzumab resistance, and resistance can be reversed with siRNA knockdown of CXCR4 or small molecule inhibitors.  Several other candidate targets to reverse trastuzumab resistance have been identified though non-biased screening approaches and are being validated in functional assays as well as through analysis of human tumors from patients on clinical trials who are receiving HER2-directed therapy and exhibit different degrees of clinical response.  Intratumoral heterogeneity can also provide a window into tumor evolution and cooperativity between oncogenic proteins and downstream mediators.  For example, HER2 and uPAR genes are both adverse prognostic markers when amplified.  We have demonstrated significant variation of gene/centromeric copy ratios of both genes from cell to cell within a given tumor, yet co-amplification is much more frequent than would be predicted based on their expected independent distributions.  These different models of functional cooperativity in carcinogenesis and bypass mechanisms in cancer resistance may point to rational combinations of targeted therapies that can be tested in the clinic.

Special Clinical Research Activities

Tanya Dorff, M.D.
Dr. Dorff has opened a trial of a combination herbal supplement in biochemically recurrent prostate cancer, looking at circulating tumor cells as a correlate.
A trial of diffusion-weighted 3T MRI in predicting pathologic stage of high risk prostate cancer will open soon. Another trial of fasting to reduce chemotherapy side effects in bladder and lung cancer is due to open.

Anthony El-Khoueiry, M.D.
Phase 1/2 Study of Brivanib Alaninate vs. Placebo in Combination with Erbitux and Irinotecan in Subjects with Metastatic Colorectal Cancer
Phase II Study of E7820 plus Cetuximab in Patients with Colorectal Cancer
Phase I Study of BMS-582664 in Combination with Full Dose Erbitux in Patients with Advanced Gastrointestinal Malignancies who Have Failed Prior Therapy

Barbara Gitlitz, M.D.
Phase II/III Study of Combretastatin A-4 Phosphate in Combination with Paclitaxel and Carboplatin in Comparison with Paclitaxel and Carboplatin Against Anaplastic Thyroid Carcinoma
Phase II Study of Apricoxib in Combination with Erlotinib in Non-Small Cell Lung Cancer Patients
Phase II Study of HKI-272 for the Treatment of Non-Small Cell Lung Cancer
Phase II Trial of Paclitaxel Carboplatin and Bevacizumab with or without PF 3512676 as First Line Treatment of Patients with Advanced Nonsquamous Non-Small Cell Lung Cancer
Phase II Study of ABT-869 in Advanced or Metastatic Non-Small Cell Lung Cancer.

Syma Iqbal, M.D.
Phase II Study of Enzastaurin with 5 FU/Leucovorin plus Bevacizumab as Maintenance Regimen Following First-Line Therapy for Metastatic Colorectal Cancer
A Randomized Phase II Study of Irinotecan plus Cetuximab with or without Enzastaurin in Patients with Recurrent Colorectal Cancer
Phase II Study of Oxaliplatin, Xeloda, and Avastin as Treatment for Patients with Advanced Colorectal Cancer
Phase II Study of Capecitabine and Gemcitabine in Patients with Metastatic Colorectal Cancer
Phase 1 and Phase 2 Clinical Trials of Cancer Chemoprevention
Intraperitoneal Floxuridine in Gastric Carcinoma

Heinz-Josef Lenz, M.D.
Molecular and Clinical Pharmacodynamic Trials
Cetuximab as a Second Line Therapy
Epidermal Growth Factor Receptor (EGFR) Gene Polymorphism as a Predictor of Clinical Outcome in Platinum-Based Chemotherapy
Early Therapeutics Development
Rectal Cancer: Molecular Markers of Outcome and Toxicity
Prostate Cancer Prevention Trial
Cetuximab Plus Cisplatin Irinotecan and Thoracic Radiotherapy (TRT) for locally advanced (non-metastatic) clinically unresectable Esophageal Cancer: A Phase II Trial with Molecular Correlates
Phase III study of Bevacizumab, in Combination with Capecitabine and Cisplatin Versus Placebo in Combination with Capecitabine and Cisplatin, as First-line Therapy in Patients with Advanced Gastric Cancer.

Jacek K. Pinski, M.D., Ph.D.
Novel Therapy for Prostate Cancer Based on the Distintegrin Contortrostatin
Prognostic Molecular Markers for Prostate Cancer
Hematologic and Solid Tumor Clinical Trials of Fenretinide

David I. Quinn, M.D.
Phase III Study of Adjuvant Oncophage versus Observation in Patients
A Multiple-Center, Open-Label, Dose Escalation Study of the Safety and Pharmacokinetics of Oral NRX 194204 Capsule Administered Daily for a Minimum of 4 Weeks in Patients with Refractory Malignancies
Phase I Trial of PS341 and Bevacizumab in Patients with Advanced or Recurrent Renal Cell Cancer with Assessment of Tissue Correlates of Response
YM155 in Subjects with Hormone Refractory Prostate Cancer (HRPC) Previously Treated with at Least One Prior Chemotherapy Regimen

Christy A. Russell, M.D.
Phase II Trial of Sunitinib in Combination with Bevacizumab and Paclitaxel in Previously Untreated Patients with Metastatic Breast Cancer (avf4057g)
Trial of Gemcitabine plus Docetaxel versus Docetaxel plus Capecitabine in Metastatic Breast Cancer in First and Second Line Patients

Darcy V. Spicer, M.D.
NSABP Breast Cancer Prevention Trial
NSABP Prevention Trials
Phase III Multicenter, Randomized, Placebo-Controlled Trial of Bevacizumab in Combination with Chemotherapy Regimens in Subjects with Previously Treated Metastatic Breast Cancer

A Phase I/II Study of Hk1-272 in Combination with Trastuzumab (Herceptin) in Subjects with Advanced Breast Cancer

Debu Tripathy, M.D.
Clinical Trials in Development:
Novel HER2-Directed Agents for Breast Cancer
Neo-Adjuvant Systemic Therapy of Breast Cancer with Imaging and Biomarker Correlative
Botanical Agents with Preclinical Efficacy in Breast Cancer