annual prostate cancer symposium February 23, 2013 The Kimmel Cancer Center, Philadelphia, PA 2nd “ Novel Therapeutic Strategies for Prostate Cancer ” Lucia Languino Dept of Cancer Biology Thomas Jefferson University

What’s new in prostate cancer research? Genetics Prevention Early detection Diagnosis Staging Treatment Surgery Radiation treatment Nutrition and lifestyle changes Hormone treatment Chemotherapy Prostate cancer vaccines Bone Pain

PROSTATE CANCER: DEVELOPING A PERSONALIZED/PRECISION MEDICINE APPROACH

Critical Issues in Prostate Cancer Risk and prevention Who needs to be treated-disease stratification Understanding and treating resistance to therapy Cardiovascular side effects of therapies

PROSTATE CANCER IS PREVENTABLE THROUGH EARLIER SCREENING AND DIAGNOSIS

Biomarkers Despite significant progress in the investigation of prostate cancer biomarkers, some men are overdiagnosed with indolent CaP while others die from aggressive disease diagnosed too late. Developing markers to identify men with indolent prostate cancer who will not be affected by disease in their lifetimes and do not need treatment. Developing markers to identify men with aggressive disease who will benefit from local therapy and those who are likely to fail local therapy and require adjuvant intervention.

Prognostic versus Diagnostic Markers Biomarkers

Biomarkers: Bodily Fluids Ongoing research: A urine test for PCA3/PSA mRNA ratio is very specific for prostate cancer and has been shown to have an excellent negative predictive value in a population of men undergoing biopsy. Developing markers to minimize the number of unnecessary prostate biopsies.

Bone Metastasis and Prostate Cancer 80% Prostate Cancer Patients have metastasis to bone. The mechanisms that promote metastasis and tumor growth in the bone are poorly understood. Prostate cancer metastasis are mixed osteoblastic and osteolytic; in contrast, to breast cancer bone metastasis, which are osteolytic. In prostate cancer, targeting αv integrins by siRNA markedly reduced PC3 xenografts in the bone (Bisanz et al).

Cilengitide Cilengitide or EMD is cyclo(Arg-Gly-Asp-D-Phe-[NMe]Val) developed by Merck [Dechantsreiter, J.Med.Chem, 1999]: –It is N-methylated modification of 1st generation  v  3- selective cyclic peptide cyclo(Arg-Gly-Asp-D-Phe-Val) or cRGDfV. –It’s 4 fold more active for  v  3 integrins than cRGDfV. Phase I safety data [Eskens, EJC, 2003]: –based on 37 patients with solid tumor –Well tolerated, no drug-related hematological toxicity –No partial or complete responses with drug alone Cilengitide increases radiosensitivity of HUVECs and non-small cell lung cancer cells in vitro. [Albert, IJROBP, 2006]

Cilengitide Merck Serono, a division of Merck KGaA, Darmstadt, Germany, has enrolled in patients in the global pivotal Phase III clinical study CENTRIC.Merck Serono, a division of Merck KGaA, Darmstadt, Germany, has enrolled in patients in the global pivotal Phase III clinical study CENTRIC. CENTRIC was designed to assess the efficacy and safety of Cilengitide in combination with standard treatment in 500 newly diagnosed glioblastoma patients. The primary endpoint of the study is overall survival.CENTRIC was designed to assess the efficacy and safety of Cilengitide in combination with standard treatment in 500 newly diagnosed glioblastoma patients. The primary endpoint of the study is overall survival. Results of parallel novel pilot Prostate Cancer studies are being evaluated at this time. Results of parallel novel pilot Prostate Cancer studies are being evaluated at this time.

Cilengitide – 7 clinical trials NCI-6735: a phase II study for non-metastatic castrate resistant prostate cancer, with PSA progression despite hormonal therapy.NCI-6735: a phase II study for non-metastatic castrate resistant prostate cancer, with PSA progression despite hormonal therapy. NCI-6372: a phase II study for asymptomatic castrate resistant metastatic prostate cancer.NCI-6372: a phase II study for asymptomatic castrate resistant metastatic prostate cancer. NABTT-0306: a phase I/II multicenter study to combine with RadioTherapy for Glioblastoma.NABTT-0306: a phase I/II multicenter study to combine with RadioTherapy for Glioblastoma.

Integrins as Therapeutic Targets As with any drug target: High investment (time and resources), high risk Current programs 25% antibodies 50% small molecules 25% other (anti-sense, RNAi, natural products)