An Early Look at New Drugs on the Horizon
Washington, DC—A first look at new cancer therapies was the focus of the 6th annual New Drugs on the Horizon symposium held as a special session at the American Association for Cancer Research (AACR) annual meeting. These new agents are still in development or the early stages of clinical testing in humans, but researchers believe their targeted mechanisms of action may lead to more effective therapies for a variety of cancers.
A 17,20-lyase inhibitor
Preliminary phase 1 clinical trial results in 27 patients with me tastatic castration-resistant prostate cancer (CRPC) are encouraging, Masuo Yamaoka, associate director of Pharmacology Research, Takeda Pharmaceutical Company Limited, Japan, told the session. Most cases of prostate cancer initially respond well to hormone therapy, but resistance can develop rapidly, leading to CRPC. Treatment options are limited and chemotherapy with docetaxel is often associated with serious adverse effects, he said.
Prostate cancer is an androgen-sensitive disease. TAK-700 was selected for its ability to inhibit 17,20-lyase, a key enzyme in androgen synthesis. Preclinical trials of TAK-700 in monkeys (both castrated and intact) showed the agent rapidly (within 1 day) inhibited androgen levels in the blood as well as testosterone and cortisol.
Phase 1 human testing found that patients treated with ≥300 mg TAK-700 twice daily had a decrease in prostate-specific antigen (PSA). The agent was well tolerated and there were no dose-limiting toxicities. The safety and efficacy of TAK-700 and the use of concomitant prednisone are being further assessed in the phase 2 portion of the study, Dr Yamaoka reported.
A 2-in-1 antibody
Genentech’s 2-in-1 antibody is designed to target epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 3 (HER3), members of the epidermal growth factor receptor family that play an important role in tumorigenesis. Numerous antibodies and tyrosine kinase inhibitors (TKIs) are commercially available against EGFR but not for HER3, which has impaired kinase activity. This third member of the family is also implicated in cancer and is a target for drug development, said Gabriele Schaefer, a scientist at the biotechnology company.
Blocking more than 1 of the receptors may be more effective in treating cancer or preventing the development of drug resistance. Dr Schaefer and her colleagues generated a “2-in-1” antibody capable of binding HER3 and EGFR with high affinity. Preclinical studies show that the antibody blocked signaling pathways in various cancer cell lines and was effective in squamous cell carcinomas of the head and neck, non–small-cell lung, colorectal, and pancreatic cancers. The 2-in-1 antibody was more effective than monospecific antibodies against the HER family.
The HER2 receptor is well known for its role in very aggressive breast cancer. HER3 plays a critical role in HER2 and EGFR-driven tumors and “is in the spotlight now” because it has been shown to mediate drug resistance, she said. Tumor model studies show that MEHD7945A may be more potent than monospecific antibodies and may even be effective in some tumor types that do not respond to existing EGFR-targeting therapies. A pilot safety study in cynomolgus monkeys comparing MEHD7945A to cetuximab administered every week for 6 weeks showed a delayed onset, lower incidence, and reduced severity of skin rash compared to cetuximab. “MEHD7945A is well tolerated” Dr Schaefer told Value-Based Cancer Care. “We also did not see any new toxicities related to MEHD7945A treatment.”
More than a Cdc7 kinase inhibitor
This agent has antitumor activity in solid and hematologic cancer models, has good oral availability, is synergistic in combination with other approved drugs, and is currently in phase 1 studies. Preclinical studies show that NMS-1116354’s unique mechanism of action makes it active on cell lines that are resistant to conventional chemotherapeutic agents, including cisplatin, Francesco Colotta, MD, PhD, vice president of Nerviano Medical Sciences in Nerviano, Italy, told the session.
Most widely used anticancer drugs target the elongation step of DNA synthesis, which invariably results in a DNA damage response. NMS-1116354 targets the initiation step of DNA replication to avoid a DNA damage response. The agent induces apoptosis in cancer cells but does not induce cell death in normal fibroblasts, he said. NMS-1116354 inhibits Cdc7 kinase, which “is involved in at least 2 key cellular processes which are relevant to cancer,” said Dr Colotta—initiation of DNA synthesis and the DNA damage response.
It also downregulates Mcl-1, a protein that cancer cells depend on for survival. Mcl-1 is associated with the mechanism for tumor resistance to treatment with different drugs, and is a key survival factor for chronic lymphocytic leukemia, multiple myeloma, acute myeloid leukemia, lymphoma, and in solid tumors such as hepatocellular carcinoma, Dr Colotta said.
Preclinical studies have shown excellent activity in several in vivo models, including breast, colon, ovary, and hematologic cancers, he reported. Two phase 1 trials are ongoing in patients with solid tumors testing different schedules of administration, one at the University of Texas in San Antonio and the other at the Institut Gustave-Roussy in Cedex, France.