At the AACR molecular targeting meeting in Boston, several key presentations have focused on lessons learned from previous kinase studies and using them to help guide future developments.
Charles Sawyers from MSKCC put together a particularly nice presentation looking at the lessons learned from CML and prostate cancer. He noted that 75% of CML patients respond to imatinib and attain a complete cytogenetic response, with only a small number, 20% relapsing by 5 years. The question is why and what can be done to change this?
Firstly, the natural course of the disease predicates that mutations will occur as the cancer finds ways to re-activate BCR-ABL in order for the leukemic cells to survive. New kinase therapies in development now target not only BCR-ABL, but also the other mutations that evolve with time. Both dasatinib and nilotinib not only have different conformations than imatinib, but also inhibit most of the other mutations that have been recognised to date. However, neither targets the T315i mutation, but fortunately other compounds in R&D including AP24534, omacetaxine and others do.
Neil Shah from UCLA also made similar points in his talk and emphasised that as more therapies become available for the treatment of CML, so the ability to personalise therapy for each patient based on their particular mutation analysis now exists by choosing a kinase that is sensitive to the mutations arising. This is especially so in CML with a growing number of drugs available either commercially or through clinical trials. This is great news for patients, because this cancer was once a death sentence but is now a chronic treatable disease that can be kept under control with targeted therapies.
Hilary Calvert from University College London discussed PARP inhibitors, which target the BRCA1 and BRCA2 mutations and also potentiate the effect of some chemotherapy drugs in vivo such as temozolomide. He covered a number of these interesting agents in development, including olaparib and AG014699, and how tumour shrinkage occurs but drug resistance ultimately ensues due to intragenic deletion activity of BRCA2. Despite platinum resistance developing in ovarian cancer, however, responses to olaparib have still been seen, so much work still needs to be done in this area to figure out what resistance mechanisms are in play and what strategies can be used to overcome them. BRCA1 and BRCA2 mutations occur in both breast and ovarian cancers, so these cancers have been the primary targets for the PARP class of drug initially and represent an interesting new approach.
Kapil Bhalla from the Georgia Cancer Center described a novel new approach in breast cancer that made me stop and think. The cancer cell is always looking for ways to survive and find alternative escape routes to achieve this despite chemotherapeutic drugs targeting it's death through apoptosis. They forced the cancer cell in the mammary fat pad of mice into autophagy, and then pulled the rug away by adding an autophagy inhibitor. This was achieved by targeting heat shock response protein with panobinostat combined with an autophagy inhibitor, thus allowing apoptosis to continue instead of being inhibited.
In this novel approach, Dr Bhalla described it succintly as,
"The panobinostat accentuates stress, causes autophagy and sets up the cell to be eliminated by autophagy inhibitors."
It will be interesting to see how this approach translates into humans and if it works, we may see more autophagy inhibitors developed that are tumour specific.
AACR have launched a series of podcasts from the meeting, including one with Charles Sawyers, which you can find here and download to listen to on your MP3 player or computer. They make for very interesting listening, especially if you were unable to attend the meeting in person.