annual prostate cancer symposiumFebruary 23, 2013 • The Kimmel Cancer Center, Philadelphia, PA

2nd

““Novel Therapeutic Strategies Novel Therapeutic Strategies for Prostate Cancerfor 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 Prognostic versus Diagnostic MarkersMarkers

Biomarkers 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 121974 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 v3-

selective cyclic peptide cyclo(Arg-Gly-Asp-D-Phe-Val) or cRGDfV.

– It’s 4 fold more active for v3 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, Merck Serono, a division of Merck KGaA, Darmstadt, Germany, has enrolled in 2011 500 patients in the global Germany, has enrolled in 2011 500 patients in the global pivotal Phase III clinical study CENTRIC. pivotal Phase III clinical study CENTRIC. •• CENTRIC was designed to assess the efficacy and safety of CENTRIC was designed to assess the efficacy and safety of Cilengitide in combination with standard treatment in 500 Cilengitide in combination with standard treatment in 500 newly diagnosed glioblastoma patients. The primary endpoint newly diagnosed glioblastoma patients. The primary endpoint of the study is overall survival.of the study is overall survival.

• • Results of parallel novel pilot Prostate Cancer studies are Results of parallel novel pilot Prostate Cancer studies are being evaluated at this time. being evaluated at this time.   

Cilengitide – 7 clinical trials

• NCI-6735: a phase II study for non-metastatic NCI-6735: a phase II study for non-metastatic castrate resistant prostate cancer, with PSA castrate resistant prostate cancer, with PSA progression despite hormonal therapy.progression despite hormonal therapy.

• NCI-6372: a phase II study for asymptomatic NCI-6372: a phase II study for asymptomatic castrate resistant castrate resistant metastatic prostate metastatic prostate cancer.cancer.

• NABTT-0306: a phase I/II multicenter study NABTT-0306: a phase I/II multicenter study to combine with RadioTherapy for to combine with RadioTherapy for Glioblastoma.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)