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14 Articles in Volume 18, Issue #2
Ask the Expert: Is there evidence to prescribe cyclobenzaprine long-term?
Challenging the Chronic Pain Personality Profile
Designer Peptide May Prevent Chemo-Induced Neuropathy
Inside the Cancer Pain Research Consortium
Intrathecal Drug Therapy for Cancer-Related Pain
Managing Cancer Pain in an Era of Modern Oncology
Mapping Complex Pain: A Case Study
Medication Overuse Headache: Inaccurate and Overdiagnosed
Pain and Fall Risk in the Elderly
Reporting Quality of Care in Cancer Pain Management
Sharing the Risk: An Update to DEA & Doctors Working Together
The Intensifying Conflict Between Opioid Control and Pain Control
Two Mobile Apps Aim to Target Patient Compliance & Safety
Why Prescribers Need to Adopt Abuse-Deterrent Opioids

Designer Peptide May Prevent Chemo-Induced Neuropathy

Researchers at the Dana-Farber Cancer Institute summarize how their recent findings¹ regarding the role of Bclw may impact future treatment of cancer patients to avert pain.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of numerous anti-neoplastic drugs and represents a frequent cause of neuropathic pain.2,3 In CIPN, chemotherapeutic agents such as platinum drugs, vinca alkaloids, and taxanes damage peripheral sensory or motor nerves and cause pain, tingling, numbness, and/or impaired motor function. Symptoms typically emerge after repeated doses of chemotherapy drugs and may persist for months or even years after cessation of treatment.2,3 Despite its prevalence, the molecular mechanisms of CIPN are not well understood, and there are no available methods for prevention or treatment. Therefore, current approaches are directed to alleviating the pain symptoms and/or reducing or even discontinuing chemotherapy.

We investigated the underlying mechanisms of chemotherapy-induced peripheral neuropathy caused by the taxane, paclitaxel, a microtubule stabilizing agent used to treat breast, ovarian, lung, and other cancers.4 We delineated a molecular cascade by which paclitaxel causes sensory neuron axon degeneration and identified the anti-apoptotic Bcl2 family member Bclw (Bcl2l2) as crucial for preventing this degeneration.1 Our study has possible implications both for the design of future preventative therapies and for identifying patients at higher risk for paclitaxel-induced neuropathy.

We found that paclitaxel acts directly on peripheral sensory axons to cause axon degeneration by reducing axonal levels of the protective protein Bclw.1 Our studies further indicated that paclitaxel treatment impedes the transport of specialized RNA granules along the microtubules in axons. These RNA granules contain the messenger RNA that encodes Bclw,5 and so paclitaxel prevents the production of Bclw protein in axons.1 Importantly, when adding extra Bclw to axons before paclitaxel exposure, we were able to prevent axon degeneration.

To determine how Bclw enables this protective effect, we identified the domain within Bclw that is responsible for preventing axon degeneration. We found that a small stapled peptide6,7 mimicking the BH4 domain of Bclw is sufficient for its protective function.4 This Bclw BH4 domain specifically binds and regulates a calcium channel (IP3R1) that is present in axons, and regulates calpain proteases that execute the axon degeneration process. Susceptibility to CIPN varies greatly among individual patients. Using a mouse model, we showed that mice lacking the Bclw protein are more susceptible to paclitaxel-induced neuropathy. Together, these results suggested a molecular mechanism for paclitaxel-induced degeneration, identified Bclw mimetics as a potential preventative treatment, and suggested that patients with higher levels of Bclw may be protected from CIPN.

In CIPN, the chemotherapy treatment that causes axonal degeneration is initiated at a known and controllable timepoint, making a preventative therapy particularly useful. Our results suggested that targeting the Bclw-IP3R1-cascade may be beneficial in preventing nerve damage before it occurs. The Bclw BH4 stapled peptide used in our research may provide a useful template for the design of future therapeutics. In addition, a more in-depth understanding of the selective interaction between Bclw and IP3R1 might inform the design of drugs that target this specific interaction, without affecting pathways required for cancer cell death. However, further preclinical studies are required to determine the therapeutic relevance of our findings. It is also crucial that any future therapies aimed at preventing axonal damage do not affect the antineoplastic efficacy of paclitaxel.

As our research identifies Bclw as an endogenous protective factor, future studies might evaluate whether patients with lower expression of Bclw in sensory nerves may be more susceptible to paclitaxel toxicity. Thus, our findings may help identify patients with increased risk for developing CIPN and provide an opportunity to relieve this toxic side effect of chemotherapy.

Last updated on: March 5, 2018
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Reporting Quality of Care in Cancer Pain Management
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