Novel Therapies Interfere with Cancer Cellʼs Circuitry
Robert H. Carlson · Oncology Times · 2002
SAN FRANCISCO—The “aberrant circuitry of cancer cells” was the target for several new therapies described here at the annual meeting of the American Association for Cancer Research. “I think the theme of this meeting and the theme of current cancer research is that we have identified some of these circuits and we are developing therapies based on inhibiting these circuits,” said Neal Rosen, MD, PhD, Head of the Department of Molecular Oncogenesis at Memorial Sloan-Kettering Cancer Center in New York City. Dr. Rosen moderated a news briefing that highlighted novel therapies reported at the AACR meeting, including TRAIL (tumor necrosis factor [TNF]-related apoptosis-inducing ligand) and farnesyl transferase inhibitors (FTIs). TRAIL When the natural molecule TRAIL binds to death receptors, rapid cell death follows in various human cancer cell lines. TRAIL suppresses the growth of TRAIL-sensitive human cancers in growing mice including breast, colon, prostate, pancreas, glioblastoma, ovarian, and cervical cancers. And in combination with some conventional chemotherapies, TRAIL suppresses tumor growth that otherwise resists treatment with TRAIL or chemotherapy alone. In vitro and animal studies have also shown that TRAIL has a very selective effect, preferentially killing tumor cells while sparing normal cells. Two speakers at the news briefing described studies combining natural dietary products with TRAIL to enhance its effects. Spicy TRAIL Mix Curcumin, the active ingredient in the Asian spice tumeric, appears to enhance cell death in androgen-sensitive lymph node carcinoma of the prostate (LNCaP) cancer cells when it interacts with TRAIL to cooperatively induce apoptosis, according to data reported by Subhash C. Gautam, PhD, Senior Staff Investigator in the Department of Internal Medicine, Division of Hematology and Oncology, at Henry Ford Health System in Detroit. The results were unexpected, Dr. Gautam remarked. “At low concentrations neither of these two agents alone produced significant cell death in LNCaP cells, but combining them together, or applying curcumin first and then exposing cells to TRAIL, we can get up to 80 percent cell death.” Curcumin is a yellow pigment isolated from the rhizome of the plant Curcuma longa Linn, known to have strong antioxidant, anti-inflammatory, chemopreventive, and growth-inhibiting activity against several tumor cell lines, he said. He speculated that curcumin as an oral supplement might sensitize drug-resistant tumors to immunotherapy with TRAIL. Dr. Gautam and colleagues have tested the two drugs in combination in other cell lines, including bladder carcinoma, normal fibroblasts and androgen-independent human prostate cancer, but so far have found that only LNCaP cells respond. Dr. Rosen commented that he does not consider a natural medicine such as curcumin to be an alternative medicine, since it binds to specific targets and interferes with specific pathways. “Through the process of evolution, Mother Nature has made compounds that interfere with these [aberrant] circuits,” Dr. Rosen said. “I think natural products are a terrific way to do cancer therapy.” Red Wine Resistance to apoptosis is a major obstacle in clinical oncology, and another natural medicine featured at the briefing appears to stop cancer growth by sensitizing tumor cells that have become resistant to TRAIL. Resveratrol is a flavanoid found in red wine that has potent anti-inflammatory and antioxidant properties. German researchers found that TRAIL and resveratrol synergize to induce apoptosis in cells derived from neuroblastoma, medulloblastoma, glioblastoma, and Ewing tumors. “We also showed that sensitivity to TRAIL-induced apoptosis may be linked to the cell cycle, as resveratrol strongly enhanced TRAIL-induced apoptosis by causing GI cell cycle arrest through induction of p2l,” said Simone Fulda, MD, Assistant Professor of Pediatrics at University Children's Hospital in Ulm, Germany, who performed the study with Klaus-Michael Debatin, MD, PhD, Chair of Pediatrics at the University. When TRAIL binds to its receptors, it rapidly triggers apoptosis, but tumor cells can evade apoptosis by a multitude of mechanisms, Dr. Fulda said. Her research focused on the mechanism regulating sensitivity or resistance of tumor cells to cytotoxic therapies. Treatment with either compound alone induced only minimal apoptosis, but in combination the two substances exerted a stronger response. Dr. Fulda explained that resveratrol interferes with the cell cycle by causing an accumulation of the ras p2l protein, a central component in the cell-signaling system that is also responsible for slowing the rate of cell division. Apoptosis can be accelerated if cells are kept in certain stages of the cell cycle, she noted. Importantly, resveratrol-induced p2l expression did not depend on wild-type p53 function, since p2l induction and sensitization for TRAIL treatment was also found in p53-null osteosarcoma cells, she said. “Resveratrol puts a break on the cell cycle, putting cells into a phase of the cell cycle that makes them suddenly become sensitive to TRAIL-induced apoptosis,” Dr. Fulda said, adding that this is the first time a link between cell-cycle regulation and apoptosis sensitivity has been shown, and that there has been a clue that two seemingly unrelated areas have some molecular interplay. TRAIL Antibody In another study, a TRAIL-related monoclonal antibody, TRA-8, achieved significant response rates alone in animal breast-cancer models when combined with standard chemotherapy agents. “The combination treatment produced a striking anti-tumor effect, but no responses were seen when the animals were treated with doxorubicin or paclitaxel alone,” said Donald J. Buchsbaum, PhD, Professor and Director of the Division of Radiation Biology, Department of Radiation Oncology, at the University of Alabama at Birmingham (UAB). He said the breast cancer tumors were approximately one half inch in diameter, and that many completely disappeared with one course of treatment. Ten out of 14 animals treated with the TRA-8 antibody plus doxorubicin had complete regression, for a complete response rate of 71 percent. The TRA-8 and paclitaxel combination had a 38% complete regression rate, and animals treated with TRA-8 alone had a regression rate of 22 percent. No regression occurred with either chemotherapy drug alone.Figure: Simone Fulda, MD, and Klaus-Michael Debatin, MD, PhDWhile TRAIL binds to two death receptors (DR4 and DR5) and two decoy receptors (DcR1 and DcR2) in the cell, TRA-8 selectively targets only one death receptor, DR5, which is primarily expressed by cancer cells but not normal cells, Dr. Buchsbaum said. This selectivity may give the TRA-8 monoclonal antibody its advantages over TRAIL, he noted. TRA-8 was developed through a partnership between the UAB Arthritis and Musculoskeletal Center and Sankyo Company, Ltd., of Tokyo. Dr. Buchsbaum said a human version of TRA-8 is being produced by Sankyo, and that clinical trials could begin in the next 12 months.Figure: Said M. Sebti, PhDFTIs Used Clinically in MDS Farnesyl transferase inhibitors (FTIs) were developed to reduce or inhibit the activity of ras, a gene that triggers tumor growth in about 30 percent of human cancers. A Phase I/II study that resulted from a collaboration between the H. Lee Moffitt Cancer Center and Research Institute and M.D. Anderson Cancer Center evaluated the FTI R115777 in patients with myelodysplastic syndrome (MDS) found the agent to be clinically active in some patients. But there was no correlation between clinical response to the drug and specific biological markers. “Preclinically in mice, this drug looks wonderful. It inhibits tumors, shrinks tumors in some models, and clearly works without toxicity,” said Said M. Sebti, PhD, Professor of Oncology, Biochemistry, and Molecular Biology and Director of the Drug Discovery Program at Moffit. The study included 21 MDS patients, and six of 18 evaluable participants had responses. But there was no relationship between response and dose level, said his collaborator, Razelle Kurzrock, MD, Professor of Medicine at M.D. Anderson. “At the molecular level the function of the FT enzyme was inhibited in the blood cells of all the patients and the molecular target was hit, but only six patients responded to the treatment,” Dr. Sebti said. “That tells us FT inhibition is needed for a response, but that by itself does not correlate with response.” Nonetheless, some of the responses have been very durable, with patients remaining on treatment for more than a year. Dr. Kurzrock noted that while a 30% response rate is modest, the responses occurred at doses that have minimal toxicity even in elderly patients. Dr. Sebti called farnesyl transferase a housekeeping protein involved in many processes. It can be inhibited to a certain degree to affect cancer cells without affecting normal cells. “We don't understand why, but it seems that some cancer cells depend absolutely on farnesylation for growth while others don't,” he said. Oncology-Times.com Check www.oncology-times.com for basic information about OT. Although the articles are available as yet only in the print edition, the Web site does have a Table of Contents list of all articles starting in January 2001.