Basic science has helped researchers and companies make discoveries that could eventually benefit cancer patients. At an AACR plenary session, Andrew Tutt of Guy's Hospital in London discussed the work being done to target DNA repair mechanisms in clinical trials, and how compounds based on this principle could be combined with chemotherapy to treat patients. There has been a lot of discussion around the basic principle of lethality, Tutt said. Cells may tolerate loss of function in some gene pathways, but not in others. If researchers can induce defects in the basic tissue repair function of PARP, this could lead to a synthetic lethal phenotype in some tumor tissues, he added. A number of PARP inhibitors are being developed, particularly those that exploit synthetic defects in BRCA 1 and 2. AstraZeneca is currently testing a compound, olaparib, that has had some success in inhibiting PARP and beating back certain cancers, Tutt said. In a proof-of-concept trial of breast cancer patients with BRCA 1 and 2 mutations, the objective response rate was 41 percent with a 400 milligram dose. In the ovarian cancer proof-of-concept trial, patients with the BRCA 1 and 2 mutations had a 33 percent response rate with the same dose. A similar trial done by Merck of their oral PARP inhibitor, MK4827, showed a 50 percent response rate in BRCA 1 and 2 breast cancer patients, and 37 percent in BRCA 1 and 2 ovarian cancer patients, Tutt added. But these drugs have to be combined with chemotherapy for maximum benefit. The drug can weaken the tumor and disable its repair mechanisms, but chemotherapy is needed to deliver the knock-out blow to eradicate the tumor. However, the chemotherapy dose does need to be adjusted, and more study is needed as to what the ideal dose of chemotherapy is when combined with these PARP inhibitors. In addition, Tutt said, these drugs also need to be combined with a companion diagnostic to identify the population that would most benefit from this type of therapy.
Genentech's Vice President of Molecular Biology, Frederic de Sauvage, said his company is making headway into developing Hedgehog pathway inhibitors to treat medulloblastoma and basal cell carcinoma. Basal cell carcinoma is the most common form of cancer in the world, and is usually benign and treatable with surgery, de Sauvage said. But in a small number of cases, basal cell carcinoma progresses to a metastatic form for which there are currently no treatments available. Researchers had a breakthrough in 1996 when they connected mutations in the PTCH and SMO genes to a breakdown in signaling in the Hedgehog pathway. About 97 percent of basal cell carcinomas exhibit this pathway signaling, and about 25 percent to 30 percent of medulloblastomas do. Genentech conducted a screen of 79,000 small molecules in its libraries and performed a cell-based assay to find out whether they inhibit the Hedgehog pathway, de Sauvage said. A genetically engineered mouse model showed that certain basal cell carcinoma topical Hedgehog pathway inhibitors led to tumor regression and shutdown of the pathway. Genentech is developing one such compound, Vismodegib, for treatment of basal cell carcinoma. In the Phase I trial, the patients enrolled responded so well that the trial was expanded to look at dose as well as safety and efficacy, de Sauvage said. A Phase II trial was recently completed, and the company is still assembling the data.