Researchers at the 101st Annual Meeting of the American Association for Cancer Research (AACR) introduced four new drugs that appear to successfully fight tumors in preclinical trials. The clinical drug possibilities revealed at the AACR meeting, held April 17-21 in Washington, DC, include NMS-1116354, a Cdc7-kinase inhibitor; a two-in-one antibody that targets EGFR and HER3; TAK-700, an inhibitor of 17,20-lyase; and NVP-BKM120, a selective inhibitor of type 1 PI3-kinases.
AACR panel co-chair Matthew A. Marx, PhD, of Pfizer, Inc, San Diego, characterized the presentations as "the first disclosure of the structures of these new clinical candidates."
NMS-1116354
Francesco Colotta, MD, PhD, of Nerviano Medical Sciences, Nerviano, Italy, described NMS-1116354 as a "potent and selective Cdc7LMW inhibitor" that "specifically induces phosphorylation of Mcm2 in Ser 40." The compound, directed toward advanced metastatic solid tumors, is involved in DNA damage response and "activated by a still partially unknown mechanism." It does not damage DNA in normal cells but induces apoptosis in solid tumor cancer cells by impairing DNA replication in those cells. The compound appears to be equally active in resistant cell lines that do not respond well to other cytotoxic agents, and in vivo it can be used in combination with widely approved anticancer drugs. NMS-1116354 appears more efficacious in tumors that are overexpressing MCL-1.
MEHD 7945A
Gabriele M. Schaefer, PhD, of Genentech, Inc, South San Francisco, discussed MEHD 7945A, an antibody combination that blocks epidermal growth factor receptor (EGFR) and HER3 and results in a blockade of the major HER family signaling pairs. The compound has a higher potency compared to monospecific antibodies and inhibits EGFR and HER3/HER2-dependent signaling, producing a combined inhibition of MAPK and PI3K. MEHD 7945A demonstrates efficacy in vivo in a broad range of tumor types, including colon, head and neck, ovarian, breast, and pancreas. In studies using cynomolgus monkeys, the animals had delayed onset, lower incidence, and fewer skin lesions with MEHD 7945A than with cetuximab (Erbitux). Moreover, no new toxicities were reported.
TAK-700
In his presentation on TAK-700, Masuo Yamaoka of Takeda Pharmaceuticals Co, Ltd, Osaka, Japan, explained that researchers used this nonsteroidal androgen synthesis inhibitor of the 17,20-lyase enzyme to treat castration-resistant prostate cancer. According to Dr. Yamaoka, preclinical studies showed that TAK-700 binds to and inhibits 17,20-lyase in both the testes and adrenal glands. Phase I/II clinical trials have commenced to investigate the efficacy of TAK-700. A phase I study, with an enrollment of 26 patients, revealed that at doses of 300 mg twice per day, TAK-700 was well tolerated in patients with metastatic castration-resistant prostate cancer. Phase II enrollment is ongoing.
NVP-BKM120
William R. Sellers, MD, of Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, presented research on NVP-BKM120, a selective type 1 PI3K inhibitor. In preclinical studies, NVP-BKM120 inhibited cell growth and induced apoptosis in a number of cell lines. Dr. Sellers indicated that NVP-BKM120 penetrates the blood-brain barrier, so it could be a drug suitable for glioblastoma and other tumors that have metastasized to the brain. In preliminary phase I data, 8 of 11 patients had metabolic partial responses.
