|T H E N I H C A T A L Y S T||M A Y J U N E 2006|
Bench-to-Bedside Journey to Morocco
TO VANQUISH INTRACTABLE
Michael Iadarola, chief of the Neurobiology and Pain Therapeutics Section, NIDCR, and anesthesiologist Andrew Mannes, who works both in Iadarola's laboratory and in the Clinical Center, are leading an effort to bring a new pain-relieving drug, called resiniferatoxin or RTX, to the clinic.
is intended for patients with advanced cancer whose pain is not alleviated by
morphine or other currently available drugs. It is almost ready for a Phase
I clinical trial, thanks in part to Iadarola's 2001
Bench-to-Bedside Award that funded critical parts of the translational work.(1 )
Opioids and Cancer Pain
Patients with advanced cancer often experience severe pain. Many, but not all, patients can control their pain with high doses of morphine and other opioidsbut at the cost of a host of debilitating side effects, including impaired consciousness, nausea, vomiting, and constipation. And for patients who do not get relief from morphine, there are not a lot of options.
Iadarola estimates that there are currently 50,000100,000 cancer patients who either cannot control their pain or have a dismal quality of life because of the side effects of their pain medication. Iadarola and Mannes hope that their novel strategy for pain relief can help this population. "We want to take pain out of the equation," says Mannes.
Opioids work by binding to receptors on pain-sensitive neurons and inhibiting transmission of pain signals to the brain. However, animals have evolved to remain sensitive to pain as long as the tissue injury remains and the pain-sensing neurons are intact. "If [the painful stimulus] is still happening at the periphery, it's going to get through the spinal cord and up to the brain one way or another," says Iadarola.
With long-term use, opioids gradually lose their effectiveness and patients need progressively higher doses to get pain relief.
Killing the Messenger
In contrast, RTX is a non-opioid, nonaddictive analgesic that works by selectively killing the neurons that are responsible for cancer pain while leaving other neurons intact. RTX, explains Iadarola, "is like a molecular scalpel."
RTX is a naturally occurring substance found in a species of a Moroccan cactus-like succulant plant. People have used latex from this cactus for topical pain relief and other medicinal purposes for thousands of years.
The molecular structure of RTX resembles that of capsaicin, the active ingredient in hot peppers.(2) RTX and capsaicin both bind to the same neuronal receptor, an ion channel called TRPV1 or the vanilloid receptor1, but RTX binds 500 to 1,000 times as tightly.
1. The Bench-to-Bedside program funded some of the initial animal work, the purchase of the initial Euphorbia resinifera latex from Morocco, and the costs of drug purification to meet FDA regulatory guidelines. Additional funding came from Iadarola's laboratory budget and, importantly, from the NIDA division headed by Frank Vocci, with which the Iadarola lab collaborated in preparing the drug for toxicologic studies.
2. The fact that RTX is a capsaicin analog was discovered in unrelated research by NCI's Peter Blumberg (see The NIH Catalyst, March-April 1997, "The Capsaicin Story: Some Like It Hot"). Blumberg was working with tumor-promoting phorbol esters and found that the non-capsaicin part of RTX has structural similarity to phorbols, though it does not have tumor-promoting actions.
3. In addition to the Bench-to-Bedside program, the primary facilitator of the research, and their NIDA collaborators, Iadarola and Mannes cite the Pharmaceutical Development Section of the NIH Pharmacy, run by George Grimes, and the NCI Protocol Review and Monitoring Committee and the NCI IRB for their help with issues related to cerebrospinal fluid volume in humans, starting-dose justification in extrapolating from animals, and dose escalation.
4. The team worked with Ahmed Benharref, of the Laboratory of Natural Chemical Products at the Université Cadi Ayyad in Marrakech, and Charles Dahan, of the United States and Morocco, who handled international coordination and export licensing. Although the plant is not endangered and the latex-collection procedure involves a gentle scoring of the skin surface that does not damage the plant, the investigators had to secure phytosanitary clearances in accordance with the Cooperative International Treaty on Endangered Species.
Capsaicin binding causes the TRPV1 channel to open briefly, allowing a limited amount of calcium and sodium ions to flow into the cell and generating the burning sensation associated with eating hot peppers. RTX, in contrast, holds the channel wide open for a long time, flooding the cell with a toxic level of calcium ions. It can also cross the plasma membrane and release calcium ions from intracellular storage compartments.
Within an hour of exposure to RTX, neurons expressing TRPV1 die, and they do not grow back. Cells that do not express TRPV1 are unaffected. Only a few types of neurons in the body express TRPV1, so the effects of RTX treatment are quite specific.
The cell bodies of TRPV1-positive neurons are found in the dorsal root ganglion, and their nerve endings are in the skin, where they respond to sensations of moderate heat, and in the internal organs, where, importantly, they appear to be the main mediators of cancer and inflammatory pain.
Iadarola and his colleagues have long been interested in clinical treatments for severe pain and in the basic science behind the sensory detection of painful stimuli (nociception) and the transmission of pain signals to the brain. (Pain in humans is a combination of nociception and higher-order sensory, psychological, and emotional responses.) Their experience in both of these areas put them in an ideal position to recognize the potential of RTX for pain relief.
On the clinical side, they were already testing strategies for specifically killing pain neurons. On the basic-science side, they were interested in TRPV1's role in the early stages of nociception.
In an effort to better understand signaling through the TRPV1 receptor, Zoltan Olah and Laszlo Karai, scientists then in Iadarola's lab, treated cells that expressed a fluorescently labeled form of TRPV1 with RTX and examined them under the microscope. To their amazement, the cells underwent a dramatic death. These studies "gave us the insight" into how RTX could work as a painkiller, says Iadarola.
After completing studies in rats that suggested that RTX was effective at reducing pain, Iadarola's lab teamed up with Dorothy Cimino-Brown, a veterinarian at the University of Pennsylvania in Philadelphia, to try RTX as a pain reliever in dogs with naturally occurring bone cancer.
Preempting Euthanasia in Dogs
The dogs enrolled in the study had severe pain that was not well controlled by available analgesic medications, and their owners were considering euthanizing them. They received a single injection of RTX into the fluid around the spinal cord so the drug would bathe the dorsal root ganglia. RTX is very painful for the first hour or so after administration, so the dogs were placed under general anesthesia for treatment.
The results were impressive. All of the dogs experienced significant pain relief that lasted for the rest of their lives. One dog that had only walked on three legs due to pain from a large tumor on his foreleg trotted almost normally through the clinic with his tail wagging several weeks after treatment. Moreover, RTX did not negatively affect locomotion, coordination, bowel and bladder function, or behavior in any of the animals.
Encouraged by the results in dogs, Iadarola and Mannes are currently developing RTX for testing in humans, which has immersed them in the complex and sometimes frustrating world of translational medicine.
Going by the Book
Before a new drug can be used in humans, researchers must obtain a very high quality batch of the drug and conduct formal toxicology studies that meet the FDA's specifications, and they must design a clinical protocol for administering it.
To meet the first requirement, the team has relied heavily on the assistance of James Terrill, of the Division of Pharmacotherapies and Medical Consequences of Drug Abuse at NIDA, who has extensive experience with the FDA's procedures and requirements for new drugs, says Iadarola. In this realm "definitions of words [such as 'impurity'] are a little bit different from the way we normally think of them," he says.
After some false starts, the group now has a batch of RTX that qualifies for use in humans. Their clinical protocol is also well on its way, awaiting final approval from the NCI's Institutional Review Board.
They expect to begin toxicology studies in the animals this summer, and if all goes well they will move on to a Phase I clinical trial in humans. Mannes is the PI and Iadarola the associate PI on the protocol, entitled "A Phase 1 study of the intrathecal administration of resiniferatoxin for treating severe refractory pain associated with advanced cancer."
They plan to enroll patients at NIH who have advanced cancer and are no longer seeking curative therapy. Although the purpose of the Phase I trial is to establish the safety and optimal dose of RTX, they hope that some of the patients in the study will also get relief from their pain.
A Fine Translation
Iadarola emphasized the importance of having a supportive environment in which to do translational research.(3) Studies that are essential to preparing a drug for the clinic are not the types of research that are rewarded by the basic-science community, he says. Iadarola praised the members of his laboratory for their independence and their ability to advance the lab's basic-science projects while he was busy with tasks such as importing 40 liters of cactus resin from Morocco's Atlas Mountains.(4)
Iadarola and Mannes are cautiously optimistic about RTX's future. "There's a [saying] around the NIH that if there was ever a mouse or a rat that had cancer or pain, we'd be able to treat it," says Mannes. While many of these seemingly successful therapies do not live up to their promise in humans, the investigators observe they have reason to hope that the therapeutic effects of RTX will be more extrapolatable.
The dramatic relief it afforded dogs with naturally occurring cancerthe clinical correlate of what could be expected based on its mechanism of actioninforms their very best guess that the drug will also be safe and effective in patients with heretofore severe intractable pain.
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