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Testing Ways to Trigger Cell Death From the Outside
Cells have two partially overlapping pathways that can induce programmed cell death. One of those branches is blocked by mutations in the p53 gene, which occur in more than half of tumors. So far scientists have been unable to find safe methods to activate the other branch.
That obstacle may be changing. Three drugs in early clinical trials are designed to activate "death receptors" on the cell's surface, the p53-independent pathway. The drugs—one small molecule and two monoclonal antibodies—appear relatively safe, and evidence from phase I and II trials suggests that the agents are active in a variety of tumor types.
"The proapoptotic death receptors represent a novel target for anticancer therapy," said Roy S. Herbst, M.D. Ph.D., chief of thoracic medical oncology at the University of Texas M. D. Anderson Cancer Center, who led the phase I trial for one of the compounds. "From a clinician's point of view, and as someone who is interested in translational research, I think this is a huge thing because we have a new class of agents."
Small-Molecule Approach
One of the novel agents is a recombinant protein called rhApo2L. The protein, which is in phase I clinical trials, is a truncated copy of the natural human molecule, called the Apo2L/TRAIL ligand, that binds to two receptors on the cell's surface. Researchers know that the receptors activate enzymes that lead to cell death.
Although the components of this system have been known for a decade, previous attempts to develop drugs against another member of this receptor family (the FAS receptor) resulted in severe liver damage in animals. No significant liver toxicity has been seen with rhApo2L in preclinical models or in the current phase I trial, even though 14 of the 58 patients in the trial had liver metastases.
The maximum tolerated dose has not yet been reached, according to data presented by Herbst at the annual meeting of the American Society of Clinical Oncology. The highest dose tested so far is 15 mg/kg of body weight/day given as a 1-hour infusion on 5 consecutive days every 3 weeks. The most common grade 3 side effects included pneumonia, high blood sugar, and elevated liver enzymes. One patient also became jaundiced because of extra bilirubin in the blood. Although several of these side effects point to potential liver toxicity, the problems may be due to the drug or to disease progression. "All patients with liver-related events also had disease progression—a very important point," Herbst said. Also, two patients with sarcoma experienced unspecified serious adverse events attributed to tumor necrosis.
Researchers were able to evaluate 37 patients, and 21 (56%) had stable disease at 8 weeks. Also, one patient with metastatic synovial chondrosarcoma had a partial response and has been allowed to remain part of the study for nearly 12 months.
Although enrollment in this single-agent trial is continuing at higher doses at five centers in the United States, the companies developing the drug—Amgen and Genentech—launched a phase Ib trial in Europe testing rhApo2L in combination with standard therapies in solid tumors and hematologic malignancies.
"We've seen some activity as a single agent and that's nice, but clearly the way these are going to work is with chemo, radiation, or something to start the cell on the way to death," Herbst said. The drug turns on the p53-independent apoptosis pathway in tissue culture, but other traditional chemotherapy agents and radiation cause DNA damage that would also induce the p53-dependent pathway. Hitting both the p53-independent and -dependent pathways may dramatically increase the power of either therapy alone, increasing the likelihood that the pro–cell death signals can overcome the anti–cell death signals that are often amplified in cancer cells.
Activating Antibodies
In addition to the small-molecule approach, two monoclonal antibodies that activate the death receptors—mapatumumab (previously HGS-ETR1) and lexatumumab (HGS-ETR2)—are in early clinical trials and have been well tolerated so far. Unlike many of the antibodies like trastuzumab already approved for cancer treatment, which inhibit the cellular protein when they bind to it, these antibodies activate the cell surface death receptors. This means that like rhApo2L, the antibodies initiate prodeath signaling in the cell in a p53-independent pathway.
Of 31 patients treated in the single phase I trial of lexatumumab, one patient experienced grade 3 vomiting and one had grade 3 elevation of a pancreatic enzyme. Fatigue was the most common grade 1 or 2 side effect, occurring in 11 patients. Ten patients (32%) had stable disease for 2 months or more, with one patient remaining stable for more than 12 months.
Mapatumumab is farther along. Researchers have already completed three phase II single-agent trials using the drug against non-Hodgkin lymphoma (NHL), non–small-cell lung cancer (NSCLC), and colorectal cancer. Three (7.5%) of the 40 patients in the NHL study showed an objective response, with one complete response and two partial responses. All the patients who responded had follicular lymphoma. Eleven follicular lymphoma patients also had stable disease. Also, 29% of the NSCLC patients and 32% of the colorectal cancer patients had stable disease.
Laura Chow, M.D., and colleagues at Colorado Health Sciences Center in Aurora showed in a phase I study that mapatumumab can be administered safely with paclitaxel and carboplatin in patients with advanced solid tumors. Of the 28 patients in the study, the most common side effects were those typically seen with the chemotherapy agents themselves, including neutropenia, thrombocytopenia, and prickling or tingling in the skin. One case of grade 3 fatigue was attributed to the antibody therapy.
In that same study, six patients (21%) showed partial responses to the combination treatment, and 13 patients (46%) had stable disease that lasted beyond 6 weeks. Chow said it was not clear how much of the response was related to the mapatumumab versus the chemotherapy alone, and she did not know whether the combination would be tested further.
In July, researchers at Nebraska Methodist Cancer Center in Omaha initiated a phase II randomized trial comparing mapatumumab in combination with bortezomib to bortezomib alone in patients with advanced multiple myeloma. Preclinical animal studies suggested that the combination induces a higher rate of tumor cell death than either agent alone.
Hitch in the Plan?
Tissue culture experiments suggest that many tumor types are sensitive to both the Apo2L/TRAIL small molecule and the monoclonal antibodies. In a breast cancer cell line, "the ligands and antibodies are effective in the [10- to 100-nm] nanomolar range, and it is very potent induction of apoptosis," said Stanley Lipkowitz, M.D., Ph.D., a senior investigator in the laboratory of cellular and molecular biology at the National Cancer Institute during a discussion of the new agents at ASCO. The response is rapid, with initial evidence of cell death apparent 5 minutes after the addition of the ligand.
Yet not all cells are sensitive to stimulation of this death receptor. The explanations for the resistance varies, but one possibility is that mutations in the p53-dependent branch of the pathway can suppress apoptosis triggered by the death receptors. "While TRAIL can initiate apoptosis directly through activation of the [death receptor and downstream caspase enzymes], many cells require activation of both the TRAIL pathway and the mitochondrial pathway," Lipkowitz said. If that conclusion is true, then resistance to any drugs using the death receptor could be an issue because of the very mutations these drugs are designed to skirt.
Those caveats aside, the agents and the early clinical results look promising, particularly in NHL, Lipkowitz said. "A wide variety of tumor cell lines have been shown to be sensitive to ligand or agonist antibodies. Importantly, the effect can be enhanced by combinations with many agents including chemotherapeutic drugs and targeted agents. I think in the long run this will be very important for the treatment of patients with these agents."
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