Curcuphenol compounds for increasing mhc-i expression

Abstract

Provided are methods of using curcuphenol compounds to increase expression of major histocompatibility complex class I (MHC-I) antigen in cells, particularly on the surface of diseased cells such as cancer cells, and thereby increase the immunogenicity of the cells. Also provided are pharmaceutical compositions that comprise curcuphenol compounds and methods of use thereof, for instance, to treat various cancers, alone or in combination with other therapies.

1 . A method for increasing major histocompatibility complex class I (MHC-I) surface expression in a cell, comprising contacting the cell with a curcuphenol compound. 
     
     
         2 . The method of  claim 1 , where MHC-I surface expression is increased by at least about 10% relative to an untreated control cell. 
     
     
         3 . The method of  claim 1 , where the cell (in its untreated state) is characterized by reduced MHC-I surface expression and optionally reduced TAP-1 expression relative to a normal or otherwise healthy cell of the same cell type. 
     
     
         4 . The method of  claim 3 , where MHC-I surface expression and optionally TAP-1 expression in the cell is increased to within about 10% of the levels of MHC-I surface expression and optionally TAP-1 expression of the otherwise normal or healthy cell of the same cell type. 
     
     
         5 . The method of  claim 1 , where the cell is a cancer cell. 
     
     
         6 . The method of  claim 5 , where the cancer cell is a metastatic cancer cell. 
     
     
         7 . The method of  claim 5 , where the cancer cell is selected from one or more of a breast cancer cell, a cervical cancer cell, a prostate cancer cell, a gastrointestinal cancer cell, a lung cancer cell, an ovarian cancer cell, a testicular cancer cell, a head and neck cancer cell, a bladder cancer cell, a kidney cancer cell, a squamous cell carcinoma, a CNS or brain cancer cell, a melanoma cell, a non-melanoma cancer cell, a thyroid cancer cell, a endometrial cancer cell, an epithelial tumor cell, a bone cancer cell, and a hematopoietic cancer cell. 
     
     
         8 . The method of  claim 7 , where the bone cancer cell is an osteosarcoma, chondrosarcoma, or a cell of the Ewing Sarcoma Family of Tumors (ESFTs). 
     
     
         9 . The method of  claim 7 , where the gastrointestinal cancer cell is an esophageal cancer cell, stomach (gastric) cancer cell, pancreatic cancer cell, liver cancer cell, gallbladder (biliary) cancer cell, small intestinal cancer cell, colorectal cancer cell, anal or rectal cancer cell, or a gastrointestinal carcinoid or stromal tumor. 
     
     
         10 . The method of  claim 7 , where the lung cancer cell is an adenocarcinoma, squamous-cell lung carcinoma, small-cell lung carcinoma, or a large-cell lung carcinoma. 
     
     
         11 . The method of  claim 7 , where the melanoma is a lentigo maligna, lentigo maligna melanoma, superficial spreading melanoma, acral lentiginous melanoma, mucosal melanomas, nodular melanoma, polypoid melanoma, desmoplastic melanoma, amelanotic melanoma, soft-tissue melanoma, or a uveal melanoma. 
     
     
         12 . The method of  claim 7 , where the hematopoietic cancer cell is a lymphoma cell, leukemia cell, or a multiple myeloma cell. 
     
     
         13 . The method of  claim 1 , where the cell is in vitro. 
     
     
         14 . The method of  claim 1 , where the cell is in a subject, and the method comprises administering the curcuphenol compound to the subject. 
     
     
         15 . The method of  claim 14 , where the subject has cancer. 
     
     
         16 . The method of  claim 15 , where the cancer is characterized by cancer cells (in an untreated state) having reduced MHC-I surface expression and optionally reduced TAP-1 expression relative to non-cancerous cells of the same cell type. 
     
     
         17 . The method of  claim 15 , where the cancer cell(s) comprise metastatic cancer cells. 
     
     
         18 . The method of  claim 17 , where the metastatic cancer cells (in an untreated state) have reduced MHC-I surface expression and optionally reduced TAP-1 expression relative to non-cancerous cells of the same cell type, or relative to non-metastatic cancer cells of the same cell type. 
     
     
         19 . The method of  claim 16 , where MHC-I surface expression and optionally TAP-1 expression in the cancer cell(s) is increased by at least about 10% relative to a control cell. 
     
     
         20 . The method of  claim 19 , where increased MHC-I surface expression and optionally TAP-1 expression increases a CTL-mediated immune response against the cancer cells. 
     
     
         21 . The method of  claim 15 , where the cancer is selected from one or more of breast cancer, cervical cancer, prostate cancer, gastrointestinal cancer, lung cancer, ovarian cancer, testicular cancer, head and neck cancer, bladder cancer, kidney cancer (e.g., renal cell carcinoma), soft tissue sarcoma, squamous cell carcinoma, CNS or brain cancer, melanoma, non-melanoma cancer, thyroid cancer, endometrial cancer, an epithelial tumor, bone cancer, and hematopoietic cancer. 
     
     
         22 . The method of  claim 21 , where the lung cancer is osteosarcoma, chondrosarcoma, or a Ewing Sarcoma Family of Tumors (ESFTs). 
     
     
         23 . The method of  claim 21 , where the gastrointestinal cancer is esophageal cancer, stomach (gastric) cancer, pancreatic cancer, liver cancer, gallbladder (biliary) cancer, small intestinal cancer, colorectal cancer, anal or rectal cancer, or gastrointestinal carcinoid or stromal tumor. 
     
     
         24 . The method of  claim 21 , where the melanoma is lentigo maligna, lentigo maligna melanoma, superficial spreading melanoma, acral lentiginous melanoma, mucosal melanoma, nodular melanoma, polypoid melanoma, desmoplastic melanoma, amelanotic melanoma, soft-tissue melanoma, or uveal melanoma. 
     
     
         25 . The method of  claim 21 , where the hematopoietic cancer is a lymphoma, leukemia, or multiple myeloma. 
     
     
         26 . The method of  claim 25 , where the lymphoma is a T-cell lymphoma, B-cell lymphoma, small lymphocytic lymphoma, mangle cell lymphoma, anaplastic large cell lymphoma (ALCL), follicular lymphoma, Hodgkin's lymphoma, or non-Hodgkin's lymphoma. 
     
     
         27 . The method of  claim 25 , where the leukemia is chronic lymphocytic leukemia (CLL), hairy cell leukemia, acute lymphoblastic leukemia, myelocytic leukemia, acute myeloid or myelogenous leukemia, or chronic myelogenous leukemia. 
     
     
         28 . The method of  claim 21 , where the brain cancer is a glioma, meningioma, pituitary adenoma, vestibular schwannoma, primary CNS lymphoma, neuroblastoma, primitive neuroectodermal tumor (medulloblastoma), or glioblastoma multiforme. 
     
     
         29 . The method of  claim 15 , comprising administering the curcuphenol compound in combination with an additional cancer therapy. 
     
     
         30 . The method of  claim 29 , where the additional cancer therapy selected from one or more of an anti-cancer agent, radiotherapy, surgery, transplantation, photodynamic therapy, symptomatic care, and antibiotic therapy. 
     
     
         31 . The method of  claim 30 , where the anti-cancer agent is selected from a small molecule and an antibody. 
     
     
         32 . The method of  claim 31 , where the small molecule is a cytotoxic, chemotherapeutic, or anti-angiogenic agent. 
     
     
         33 . The method of  claim 32 , where the small molecule cytotoxic, chemotherapeutic, or anti-angiogenic agent is selected from one or more of alkylating agents, anti-metabolites, anthracyclines, anti-tumor antibiotics, platinums, type I topoisomerase inhibitors, type II topoisomerase inhibitors, vinca alkaloids, and taxanes. 
     
     
         34 . The method of  claim 31 , where the small molecule is selected from one or more of chlorambucil, cyclophosphamide, cilengitide, lomustine (CCNU), melphalan, procarbazine, thiotepa, carmustine (BCNU), enzastaurin, busulfan, daunorubicin, doxorubicin, gefitinib, erlotinib idarubicin, temozolomide, epirubicin, mitoxantrone, bleomycin, cisplatin, carboplatin, oxaliplatin, camptothecins, irinotecan, topotecan, amsacrine, etoposide, etoposide phosphate, teniposide, temsirolimus, everolimus, vincristine, vinblastine, vinorelbine, vindesine, CT52923, paclitaxel, imatinib, dasatinib, sorafenib, pazopanib, sunitnib, vatalanib, geftinib, erlotinib, AEE-788, dichoroacetate, tamoxifen, fasudil, SB-681323, semaxanib, donepizil, galantamine, memantine, rivastigmine, tacrine, rasigiline, naltrexone, lubiprostone, safinamide, istradefylline, pimavanserin, pitolisant, isradipine, pridopidine (ACR16), tetrabenazine, bexarotene, glatirimer acetate, fingolimod, and mitoxantrone, including pharmaceutically acceptable salts and acids thereof. 
     
     
         35 . The method of  claim 31 , where the antibody is selected from one or more of 3F8, 8H9, abagovomab, adecatumumab, afutuzumab, alacizumab (pegol), alemtuzumab, altumomab pentetate, amatuximab, anatumomab mafenotox, apolizumab, arcitumomab, bavituximab, bectumomab, belimumab, bevacizumab, bivatuzumab (mertansine), brentuximab vedotin, cantuzumab (mertansine), cantuzumab (ravtansine), capromab (pendetide), carlumab, catumaxomab, cetuximab, citatuzumab (bogatox), cixutumumab, clivatuzumab (tetraxetan), conatumumab, dacetuzumab, daclizumab, dalotuzumab, detumomab, drozitumab, ecromeximab, edrecolomab, elotuzumab, enavatuzumab, ensituximab, epratuzumab, ertumaxomab, etaracizumab, farletuzumab, FBTA05, figitumumab, flanvotumab, galiximab, gemtuzumab, ganitumab, gemtuzumab (ozogamicin), girentuximab, glembatumumab (vedotin), ibritumomab tiuxetan, icrucumab, igovomab, indatuximab ravtansine, intetumumab, inotuzumab ozogamicin, ipilimumab (MDX-101), iratumumab, labetuzumab, lexatumumab, lintuzumab, lorvotuzumab (mertansine), lucatumumab, lumiliximab, mapatumumab, matuzumab, milatuzumab, mitumomab, mogamulizumab, moxetumomab (pasudotox), nacolomab (tafenatox), naptumomab (estafenatox), narnatumab, necitumumab, nimotuzumab, nivolumab, Neuradiab® (with or without radioactive iodine), NR-LU-10, ofatumumab, olaratumab, onartuzumab, oportuzumab (monatox), oregovomab, panitumumab, patritumab, pemtumomab, pertuzumab, pritumumab, racotumomab, radretumab, ramucirumab, rilotumumab, rituximab, robatumumab, samalizumab, sibrotuzumab, siltuximab, tabalumab, tanezumab, taplitumomab (paptox), tenatumomab, teprotumumab, TGN1412, ticilimumab, trastuzumab, tremelimumab, tigatuzumab, TNX-650, tositumomab, TRBS07, tucotuzumab (celmoleukin), ublituximab, urelumab, veltuzumab, volociximab, votumumab, and zalutumumab, including antigen-binding fragments thereof. 
     
     
         36 . The method of  claim 1 , where the curcuphenol compound is selected from a compound of Formula I-A, Formula I-B, Formula II, Formula III, Formula IV, and Formula V, or a mixture thereof. 
     
     
         37 - 39 . (canceled) 
     
     
         40 . A composition, comprising a pharmaceutically acceptable carrier, an anti-cancer agent, and a curcuphenol compound or pharmaceutically-acceptable salt thereof.