The role of trophic factors in chemotherapy-induced peripheral neuropathies

Roma 22 giugno 2006

 

Guido Cavaletti

 Department of Neurosciences and Biomedical Technologies

University of Milan "Bicocca"

Monza, Italy

•several neurotrophic factors are crucial not only in the developmental stage of the central and peripheral nervous system, but also during injury and repair

•neurotrophic factors act on the nervous system cells by means of specific receptors, which can be up- and down-regulated during the course of a neurological disease

•modifications in the receptors’ expression have been demonstrated in peripheral neuropathies

•these receptors (despite, in most cases, not being restricted to the nervous system) are differentially expressed in other normal and pathological tissues

•the development of new delivery systems and more effective production methods allow a large number of patients to be treated

Trophic factors have been evaluated for the treatment of

•diabetic polyneuropathy

•painful neuropathies (HIV)

•hereditary neuropathies

•ischemic neuropathy

•chemotherapy-induced neuropathies

Neurotrophins

VEGF

IGF-1/insuline

LIF

Neuroactive steroids

Erythropoietin

Clinical trials:

NT-3: tolerable, Ph1 never published

BDNF: Ph2, not effective

Ann Neurol. 1995 Jul;38(1):30-7.

Neurotrophin-3 reverses experimental cisplatin-induced peripheral sensory neuropathy.

Gao WQ, Dybdal N, Shinsky N, Murnane A, Schmelzer C, Siegel M, Keller G, Hefti F, Phillips HS, Winslow JW

Department of Neuroscience, Genentech Inc, South San Francisco, CA 94080, USA

Phase II study ongoing in chemotherapy-induced neuropathy (?)

CDDP

3 mg/kg twice weekly x 6 w

About 50% of rats died

Vectors injected sc 3 days before starting CDDP administration

Gene Transfer was accomplished with plasmid DNA expressing

human VEGF165

Arch Neurol. 2001 May;58(5):761-8.

Improvement in chronic ischemic neuropathy after intramuscular phVEGF165 gene transfer in patients with critical limb ischemia.

Simovic D, Isner JM, Ropper AH, Pieczek A, Weinberg DHUniversity School of Medicine, Boston, Mass

•open-label, dose-escalating trial•angiographically proven critical leg ischemia •injections of phVEGF(165) human plasmid in the muscles of the ischemic limb. •testing before treatment and at 3 and 6 months. •of 29 consecutive patients enrolled, 17 (19 limbs) completed the 6 months of study

•compared with baseline studies, treated patients had significant clinical improvements in the symptom score, sensory examination score, total examination score, peroneal motor amplitude, and quantitative vibration threshold •no clinical, electrophysiologic, or vascular improvements were observed in untreated legs.

CONCLUSIONS: Ischemic neuropathy might be a reversible condition, and therapeutic angiogenesis might be an effective treatment. The presence of diabetes does not preclude a response to this therapy.

•idiopathic, painful, small fiber predominant peripheral neuropathy •double-blind, placebo-controlled design, 40 patients were randomized to treatment with recombinant human IGF-I (0.05 mg/kg twice daily by subcutaneous injection) or placebo for 6 months.

•no significant adverse events

•primary outcome measure: change in score on an analog pain scale.•secondary endpoints: quantitative sensory testing

quantitative autonomic testing neuropathy impairment scorenerve conduction studiesneuropathy symptom and change score

•no significant difference in the primary and secondary endpoints between the two groups

Co-activation of IGF-1 receptors?Direct action on other, specific receptors?

PURPOSE: To determine whether recombinant human leukemia inhibitory factor (rhuLIF, AM424, emfilermin) can prevent or ameliorate the development of chemotherapy-induced peripheral neuropathy (CIPN) after treatment with carboplatin (AUC 6) and paclitaxel (175 mg/m(2) over 3 hours).

EXPERIMENTAL DESIGN: Randomized double-blind placebo-controlled phase II clinical trial. The primary end point was a standardized composite peripheral nerve electrophysiology (CPNE) score, Secondary efficacy end points included CPNE score at last cycle and at exit evaluation, vibration perception threshold, H-reflex latency, symptom scores, and quantitative assessment of neurologic signs. Study drug was given s.c. daily for 7 days starting the day before chemotherapy. Patients were randomized to receive low-dose rhuLIF (2 microg/kg), high-dose rhuLIF (4 microg/kg), or placebo.

RESULTS: Patients (n = 117) were randomized across seven neurology test centers. rhuLIF was well tolerated with 95% compliance and no adverse effects on quality of life. No differences between groups in CPNE or any of the individual neurologic testing variables were observed.

CONCLUSIONS: rhuLIF is not effective in preventing CIPN caused by carboplatin and paclitaxel .

Clin Cancer Res. 2005 Mar 1;11(5):1890-8.

A randomized, double-blinded, placebo-controlled phase II trial of recombinant human leukemia inhibitory factor (rhuLIF, emfilermin, AM424) to prevent chemotherapy-induced peripheral neuropathy.

Davis ID, Kiers L, MacGregor L, Quinn M, Arezzo J, Green M, Rosenthal M, Chia M, Michael M, Bartley P, Harrison L, Daly M.Austin Health, Studley Road, Heidelberg, Victoria 3084, Australia. Ian.Davis@ludwig.edu.au

PURPOSE: To determine whether recombinant human leukemia inhibitory factor (rhuLIF, AM424, emfilermin) can prevent or ameliorate the development of chemotherapy-induced peripheral neuropathy

(CIPN) after treatment with carboplatin (AUC 6) and paclitaxel (175 mg/m2) over 3 hours).

EXPERIMENTAL DESIGN: Randomized double-blind placebo-controlled phase II clinical trial. The primary end point was a standardized composite peripheral nerve electrophysiology (CPNE) score, based on nerve velocities and amplitudes, measured at baseline and after four cycles of chemotherapy. Secondary efficacy end points included CPNE score at last cycle and at exit evaluation, vibration perception threshold, H-reflex latency, symptom scores, and quantitative assessment of neurologic signs. Study drug

was given s.c. daily for 7 days starting the day before chemotherapy. Patients were randomized to receive low-dose rhuLIF (2 microg/kg), high-dose rhuLIF (4 microg/kg), or placebo.

RESULTS: Patients (n = 117) were randomized across seven neurology test centers. rhuLIF was well tolerated with 95% compliance and no adverse effects on quality of life. No differences between groups in CPNE or any of the individual neurologic testing variables were observed.CONCLUSIONS: rhuLIF is not effective in preventing CIPN caused by carboplatin and paclitaxel.

2 microg/kg rat = 11.8 microg/m2

2 microg/kg humans = 74 microg/m2

correct conversion from rats to humans = 0.32 microg/kg

“Peripheral nerves synthesize neuroactive steroids and express both classical and non-classical steroid receptors which are able to interact with them.

Due to this capability, peripheral nerves and particularly, their glial component, the Schwann cells, respond to neuroactive steroids with changes in cell proliferation and the elaboration of cellular products (e.g., myelin membranes, myelin proteins, transcription factors involved in the myelination process, etc.).”

Evaluated also in•aging•diabetes

“The majority of drugs developed for neurologicindications fail because they are not clinically tolerated.

A sensible strategy, therefore, is to explorethe efficacy of drugs in the nervous system that havealready been approved for other indications.

When I was in medical school, erythropoietin was known to be a cytokine produced in the kidney and wasthought to be important only for the developmentof red cells, which bear receptors for erythropoietin.

But recent results have shown that nerve cellsalso have erythropoietin receptors and that thiscytokine is made in the nervous system and canfunction as a neuroprotective agent.”

EPOr agonists

“Tumor vasculature is essential for the survival, growth and metastasis of the tumors, since it supplies cancer cells with nutrients and oxygen . We and others have reported that normal and tumor endothelial cells express EPOR, and EPO may stimulate the proliferation and migration of these cells.Furthermore, EPO stimulates angiogenesis both in vitro and in vivo animal models. Since the majority of chemotherapeutic drugs target mostly highly proliferating cells, EPO may stimulate tumor endothelial cells and make them more susceptible to chemotherapeutic treatment resulting in the collapse of tumor vasculature and the subsequent deprivation of oxygen and nutrients for the tumor. In such case, EPO and the combined hemotherapeutic drug may act as an antiangiogenic agent.

Bohlius J et al.

EPO for patients with malignant disease (Cochrane Review)In: The Cochrane Library, Issue 3, 2004

“As compared to placebo or no treatment, there was some evidence for EPOto improve tumor response (RR 1.36, 95%CL 1.07-1.72, seven trials, n=1150)”

“In conclusion, the data available for this analysis are not sufficient to provide evidence for a positive effect of EPO on tumor response”