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Novel Therapeutic Strategies for Prostate Cancer

• Lucia Languino Dept of Cancer BiologyThomas
  Jefferson University

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Whats 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

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PROSTATE CANCER DEVELOPING A PERSONALIZED/PRECIS
ION MEDICINE APPROACH
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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

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PROSTATE CANCER IS PREVENTABLE THROUGH EARLIER
SCREENING AND DIAGNOSIS
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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.

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Biomarkers

• Prognostic versus Diagnostic Markers

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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.

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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
av integrins by siRNA markedly reduced PC3
xenografts in the bone (Bisanz et al).
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Cilengitide

• Cilengitide or EMD 121974 is cyclo(Arg-Gly-Asp-D-P
  he-NMeVal) 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.
• Its 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

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Cilengitide

• Merck Serono, a division of Merck KGaA,
  Darmstadt, Germany, has enrolled in 2011 500
  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.
• Results of parallel novel pilot Prostate
  Cancer studies are being evaluated at this time.
•  

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Cilengitide 7 clinical trials

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

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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)