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Journal of Clinical Oncology, Vol 25, No 19 (July 1), 2007: pp. 2858-2859 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.11.7358
Sunitinib Malate and Multiple Receptor Tyrosine Kinases Inhibitors: Are They Also Novel Drugs for Chronic and Neurophatic Pain?Ospedale "G.RUMMO" Benevento, Piedimonte Matese, Italy To the Editor: Recently, I read with interest the article "Sunitinib: From Rational Design to Clinical Efficacy"1 published in the March 1, 2007, issue of the Journal of Clinical Oncology. Interestingly, Chow et al reported a range of in vitro and in vivo RTK (RTKs are transmembrane proteins at the cell surface that transduce extracellular signals to the cytoplasm, which may be inhibited by sunitinib) targets that have been further validated by the clinical activity observed in patients treated with sunitinib and other agents inhibiting these pathways. "However," they added, "the contribution and/or dominance of inhibition of which specific RTK pathways are associated with sunitinib-induced responses are not well understood and are under active investigation."1 The authors reported data on preclinic and clinic phase I, II, and III trials. They correctly concluded that although initially promising, RTK targets need additional validation in phase II/III trials. Overall, they said, the clinical benchmarking of an agent that influences multiple signaling pathways of tumor, stromal, and endothelial compartments should stimulate additional research into the biology of responsive tumors. Challenges ahead include the ability to combine sunitinib with other therapies where toxicities may be overlapping, optimization of dosing regimens, and additional assessment and development of patient selection criteria. Reading this interesting article, I recalled another recently published article2 where the authors discussed how the past decade has been characterized by a better understanding of physiology of chronic pain. These other authors reported that nerve-growth factor (NGF),2 "the founding member of the neurotrophin family of structurally related secreted proteins, binds to two types of receptors: a common receptor, p75NTR, which binds all neurotrophins with a similar affinity, and members of the trk family of receptor tyrosine kinases (trkA, trkB, and trkC), which bind different neurotrophins. trkA is the receptor tyrosine kinase for NGF."3,4 trkA mediates the survival-promoting and neurite growth-promoting effects of NGF during development and its later pain-provoking actions.5 A lot has been written about chronic pain: synaptic events, axonal reflexes leading to wind-up processes, and the key roles played by AMPA receptors, NMDA and brain-derived neurotrophic factor receptors and mediators.2 NGF has also been proven to play a role in chronic pain, but unfortunately, research has hindered the recognition of the role of NGF as a key pain mediator until recently.2 So, drug-discovery approaches to NGF antagonists became the real target of several researchers. These recent findings suggest that there is an effective therapeutic need to prevent the activation of trkA by NGF. Namely, Hefti et al2 remarked that this might be achieved by agents that remove free NGF by molecules that prevent NGF binding to trkA and by molecules that prevent activation of trkA. As in pain medicine, in oncology, molecules that prevent activation of trkA have become the target and the article by Chow et al remarkably underlines how receptor tyrosine kinase inhibitors provide novel biologic insights that have created the concept of patient selection for these diseases. As we all know, sunitinib malate (formerly SU11248), the first oral drug acting as a multitarget tyrosine kinases inhibitor, has been approved for the treatment of gastrointestinal stromal tumors and renal cell carcinoma,6,7 and several authors recalled how the combination of sunitinib and other molecules (eg, RAD001) represent a promising novel treatment strategy against tumors.1,8 In chronic cancer pain the mRNA expression of NGF receptors for trkA have been already examined4 and several authors reported that NGF receptors were found in all tumor specimens. In the cited study4 trkA was negatively correlated and associated with abdominal or back pain and perineural invasion. Regarding this, patients with high trkA expression levels exhibited more frequent perineural invasion and a higher degree of pain. Several pharmaceutical companies have active drug-discovery and development programs that are based on a variety of approaches to antagonize NGF, including NGF capture, blocking the binding of NGF to trkA and inhibiting trkA signaling. NGF antagonism is expected to be a highly effective therapeutic approach in many painful phases, and to be free of the adverse effects of traditional analgesic drugs. As already reported by Hefti et al,9 receptor tyrosine kinases are highly attractive drug targets. Several cancer drugs and drug candidates that inhibit the function of the receptor tyrosine kinases for particular growth factors are being evaluated currently. Most of these inhibitors block the binding of adenosine triphosphate to the catalytic tyrosine kinase domain.10 The alkaloid K252a inhibits trk signaling with high potency and attenuates hypersensitivity in an animal model of pancreatic pain.11,12 However, lack of selectivity for trkA means that K252a is not a viable drug candidate because it is likely to have many adverse effects that are unrelated to inhibition of trkA. Given the large number of tyrosine kinase receptors, it might be difficult to identify a potent antagonist of trkA with the selectivity that is necessary for chronic treatment of patients both for cancer and pain. As Chow et al concluded,1 the clinical benchmarking of an agent that influences multiple signaling pathways of tumor stromal and endothelial compartments should stimulate additional research and maybe several researchers actually involved in late stages of sunitinib trials should be encouraged to focus attention also on eventual pain relief. We are very curious to know if Chow et al, Dr Haller, or readers are aware of eventual sunitinib effects on NGF/trk binding that could validate them playing role also for chronic pain and encourage pharmaceutical companies involved in pain versus similar multitarget agents. Our hope is that good novel agents could come soon from researchers involved in conclusive evaluations of multiple receptor tyrosine kinase inhibitors, such as as sunitinib. AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. REFERENCES
1. Chow LQ, Eckhardt SG: Sunitinib: From rational design to clinical efficacy. J Clin Oncol 25:884-896, 2007 2. Hefti FF, Rosenthal A, Walicke PA, et al: Novel class of pain drugs based on antagonism of NGF trends. Pharmacological Sciences 27:85-91, 2006[CrossRef] 3. Le Bars D, Willer JC: Physiology of Pain [Italian]. Encyclopédie Médico-Chirurgicale (Elsevier SAS, Paris) Anesthesia & IC, 36-020-A-10, 2005 4. Pareek TK, Keller J, Kesavapany S, et al: Cyclin-dependent kinase 5 activity regulates pain signaling. Proc Natl Acad Sci U S A 103:791-796, 2006 5. Huang EJ, Reichardt LF: Trk receptors: Roles in neuronal signal transduction. Annu Rev Biochem 72:609-642, 2003[CrossRef][Medline] 6. Motzer RJ, Michaelson MD, Redman BG, et al: Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin Oncol 24:16-24, 2006 7. Motzer R, Rini B, Michaelson M, et al: Phase II trials of SU11248 show antitumor activity in second-line therapy for patients with metastatic renal cell carcinoma (RCC). J Clin Oncol 24:380s, 2006 (abstr 4508) 8. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology: Kidney Cancer (version 2.2007). http://www.nccn.org/professionals/physician_gls/PDF/kidney.pdf 9. Ikezoe T, Nishioka C, Tasaka T, et al: The antitumor effects of sunitinib (formerly SU11248) against a variety of human hematologic malignancies: Enhancement of growth inhibition via inhibition of mammalian target of rapamycin signaling. Mol Cancer Ther 5:2522-2530, 2006 10. Madhusudan S, Ganesan TS: Tyrosine kinase inhibitors in cancer therapy. Clin Biochem 37:618-635, 2004[CrossRef][Medline] 11. Winston JH, Toma H, Shenoy M, et al: Acute pancreatitis results in referredmechanical hypersensitivity and neuropeptide up-regulation that canbe suppressed by the protein kinase inhibitor k252a. J Pain 4:329-337, 2003[CrossRef][Medline] 12. Dang C, Zhang Y, Ma Q, et al: Expression of nerve growth factor receptors is correlated with progression and prognosis of human pancreatic cancer Gastroenterol Hepatol 21:850-858, 2006
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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