Hilary Calvert - Overview
The CRC Developmental Therapeutics Programme in Newcastle
is a multidisciplinary translational research programme that seeks to:
- Identify and validate targets for therapeutic exploitation using clinical
tumour material.
- Undertake rational drug discovery and development to exploit novel
targets.
- Perform mechanism-based clinical trials to evaluate new agents, and
optimise existing therapies using molecular pathological and pharmacological
parameters.
The CRC Programme is the focal point for cancer research
in Newcastle, and was the catalyst for the formation of the Northern Institute
for Cancer Research (NICR) in 2001.
Research Highlights
Identification of targets for therapeutic exploitation from molecular
pathological studies of tumour material and development of appropriate
assays.
We have established and implemented cell-free and whole cell assays for
the MDM2-p53 interaction and MYCN-mediated transcription. We have also
identified potential therapeutic targets: MYCN locus on chromosome 2p24
(neuroblastoma, alveolar rhabdomyosarcoma and small cell lung cancer),
c-erbB family members in medulloblastoma and EGF-receptor in bladder cancer
and mesothelioma.
Development of novel drugs for clinical evaluation and lead inhibitors
of new targets.
A potent inhibitor of the DNA repair enzyme poly(ADP-ribose) polymerase
has been developed for clinical evaluation. Lead inhibitors of cyclin-dependent
kinases 1 and 2, DNA-dependent protein kinase and nucleobase transport
have been synthesised and tested, as have isoindolinone antagonists of
the MDM2-p53 interaction.
Clinical Trials
We have participated in 50 clinical trials during the last five years,
including: CRC Phase I/II trials – 4, pharmaceutical company Phase I/II
studies – 22, EORTC/NCI Canada studies – 6, in house Phase I/II studies
– 3, Phase III trials – 9, pharmacological/mechanistic studies – 5.
Of particular interest is the completion of a Phase
I clinical trial of pemetrexed (Alimta(TM), MTA, LY231514) plus carboplatin
in malignant mesothelioma (40% confirmed response rate) and the progress
of a prospective trial in ovarian cancer to investigate the effect of
molecular pathology, especially p53 mutation status, on the response to
carboplatin and paclitaxel as single agents.
Priorities for the near future
Increased integration of the CRC Programme within the Newcastle Institute
for Cancer Research will allow expansion of the level of target discovery
and exploitation for drug development projects. We plan a number of translational
clinical research projects, particularly in the areas of ovarian cancer,
mesothelioma, breast cancer, sarcoma and bladder cancer. A major new initiative
focussed on the development of drugs to treat prostate cancer as part
of the MRC/NCRI Prostate Cancer programme has been started.
