Egfr targeted therapy of neurological disorders and pain

Abstract

The present invention relates to compositions and methods for treatment of neurological disorders. In particular, the present invention relates to the epidermal growth factor receptor (EGFR) as a clinical target for treatment of neurological disorders, preferably in conjunction with neuropathic pain. The invention relates in more detail to compositions comprising inhibitors of EGFR

1 . A method of treating a subject with pain associated with a neurological disease and/or cancer disease comprising administering to said subject an agent that inhibits at least one biological function of EGFR, wherein said pain is neuropathic pain selected from the group consisting of non-compressive neuropathic pain, compressive neuropathic pain, toxic neuropathic pain, metabolic neuropathic pain, traumatic neuropathic pain, autoimmune neuropathic pain, infectious neuropathic pain, and congential or hereditary neuropathic pain. 
     
     
         2 . The method of  claim 1 , wherein the pain is associated with pain nerve fiber type A, and/or B, and/or C. 
     
     
         3 . The method of  claim 1 , wherein, wherein the pain is associated with myelinated nerve fibers. 
     
     
         4 . The method of  claim 1 , wherein said compressive neuropathic pain is non-cancer related. 
     
     
         5 . The method of  claim 1 , wherein said compressive neuropathic pain is cancer related. 
     
     
         6 . The method of  claim 1 , wherein said compressive neuropathic pain is pain associated with a syndrome selected from the group consisting of failed back surgery syndrome, carpal tunnel syndrome, compartment syndrome and sciatica. 
     
     
         7 . The method of  claim 1 , wherein said toxic neuropathic pain is chemotherapy-induced peripheral neuropathy. 
     
     
         8 . The method of  claim 7 , wherein said toxic neuropathic pain is selected from pain associated with exposure to an agent selected from the group consisting of lead, arsenic, asbestos, isoniazid and thallium. 
     
     
         9 . The method of  claim 8 , wherein said toxic neuropathic pain is associated with a cancer-related chemotherapy. 
     
     
         10 . The method of  claim 1 , wherein said metabolic neuropathic pain is selected from pain associated with painful diabetic neuropathy, nutritional deficiency, alcohol induced neuropathy and thiamine deficient axonal sensorimotor burning neuropathy. 
     
     
         11 . The method of  claim 1 , wherein said traumatic neuropathic pain is associated with a syndrome selected from the group consisting of phantom limb syndrome and complex regional pain syndrome. 
     
     
         12 . The method of  claim 1 , wherein said autoimmune neuropathic pain is selected from the group consisting of chronic inflammatory demyelinating polyneuropathy and vasculitic neuropathy. 
     
     
         13 . The method of  claim 1 , wherein said infectious neuropathic pain is selected from the group consisting of postherpetic neuralgia and painful HIV-distal sensory polyneuropathy. 
     
     
         14 . The method of  claim 1 , wherein said agent reduces or modulates symptoms of said pain, wherein said symptom is selected from the group consisting of shooting pain, burning pain, tingling, numbness and combinations thereof. 
     
     
         15 . The method of  claim 1 , wherein said method provides for the long term palliative care of a subject. 
     
     
         16 . The method of  claim 15 , wherein said long term palliative care is for a period selected from the group consisting of longer than six months, longer than 12 months, longer than 24 months, longer than 36 months, longer than 48 months and longer than 60 months. 
     
     
         17 . The method of  claim 1 , wherein said method provides for reduction of the dosage of opioid agents for a subject by at least 50% compared to the subject not treated with said EGFR inhibiting agent. 
     
     
         18 . The method of  claim 1 , wherein the dosage of said following initial administration of said agent is reduced by 10-50%. 
     
     
         19 . The method of  claim 1 , wherein said agent is an anti-EGFR antibody or a biologically active portion thereof. 
     
     
         20 . The method of  claim 19 , wherein said anti-EGFR antibody is selected from the group consisting of cetuximab, matuzumab, necitumumab, nimotuzumab, panitumumab, and zalutumumab. 
     
     
         21 . The method of  claim 20 , wherein said antibody is selected from the group consisting of cetuximab or panitumumab. 
     
     
         22 . A method of  claim 20 , wherein said anti-EGFR -antibody or biologically active fragment thereof is administered every 5 to 20 days. 
     
     
         23 . The method of  claim 22 , wherein said antibody or biologically active fragment thereof is administered at an initial dose of about 300 to 500 mg per square meter, followed by an infusion of about 100 to 500 mg per square meter. 
     
     
         24 . The method of  claim 22 , whereon said antibody is cetuximab and said administration to the subject is every 5 to 10 days. 
     
     
         25 . The method of  claim 22 , wherein said antibody is panitumumab and said administration to the subject is every 10 to 20 days. 
     
     
         26 . The method of  claim 19 , wherein the initial dose causes pain reduction of 50-100% compared to the untreated subject within less than 4-8 h after administration. 
     
     
         27 . The method of  claim 1 , wherein said agent is a small molecule drug. 
     
     
         28 . The method of  claim 27 , wherein said small molecule drug is selected from the group consisting of afatinib, erlotinib, gefitinib, lapatinib, and neratinib. 
     
     
         29 . The method of  claim 27 , wherein said small molecule drug is administered orally in a dose of 10-300 mg every 1-3 days. 
     
     
         30 . The method of  claim 29 , wherein said small molecule drug is erlotinib and geftinib, and said administration is 100-300 mg in an initial dose, and 10 to 200 mg in a subsequent daily dose. 
     
     
         31 . The method of  claim 1 , wherein said administration comprises at least an initial administration of an anti-EGFR antibody or o biologically active portion thereof followed by administration of a small molecule inhibitor of EGFR. 
     
     
         32 . The method of  claim 1 , wherein said EGFR inhibiting agent is co-administered with at least an analgesic drug, selected from the group consisting of non-steroidal anti-inflammatory drugs, steroidal anti-inflammatory drugs, paracetamol, COX-2 inhibitors, opioids and cannibinoids, flupirtine, specific agents such as pregabalin and gabapentin, wherein said analgesic drug is administered in amount which is reduced by 10-100%, preferably by 50-90% compared to the subject which is not treated with said EGFR inhibiting agent. 
     
     
         33 - 44 . (canceled)