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(12) Patent Application Publication (10) Pub. No.: US 2010/0152243 A1 Haraldsson Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2010/0152243 A1 Haraldsson Et Al US 20100152243A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0152243 A1 Haraldsson et al. (43) Pub. Date: Jun. 17, 2010 (54) TREATMENT OF RENAL CELL Publication Classification CARCINOMA (51) Int. Cl. (76) Inventors: Börje Haraldsson, Landvetter A61K 3/444 (2006.01) (SE); Ulf Nilsson, Gothenburg (SE): A6IP35/00 (2006.01) Lisa Buvall, Lerum (SE); Jenny Nyström, Gothenburg (SE) (52) U.S. Cl. ........................................................ S14/334 Correspondence Address: LYNN E BARBER PO BOX 16528 FORTWORTH, TX 76162 (US) (57) ABSTRACT Methods are provided of treating renal cancer by administra (21) Appl. No.: 12/586,849 tion of certain 3.3',4,4-tetrahydroxy-2,2'-bipyridine-N,N'-di (22) Filed: Sep. 29, 2009 oxide compounds, especially 3,3',4,4-tetrahydroxy-2,2'-bi pyridine-N,N'-dioxide (Orellanine), using particular Related U.S. Application Data administration protocols and dosing regimens, as well as (60) Provisional application No. 61/195.312, filed on Oct. pharmaceutical compositions Suitable for use in the treatment 6, 2008. methods that are provided. Patent Application Publication Jun. 17, 2010 Sheet 1 of 8 US 2010/0152243 A1 to attoo/pehea. Ace? Patent Application Publication Jun. 17, 2010 Sheet 2 of 8 US 2010/0152243 A1 } uoqueqnou?auquerrauojo»?aawaauouængesuedo-99/ Patent Application Publication Jun. 17, 2010 Sheet 4 of 8 US 2010/0152243 A1 w‘914 josºsopp3?eadauzJe??eA?I?qe?ASOMOO (£=u)auquelleloluu/ºrioz enxa?sop3|3u?Suzzasopeu?kaqvzesop Patent Application Publication Jun. 17, 2010 Sheet 5 of 8 US 2010/0152243 A1 p2 Rb (Ser795) Rb (Ser807/8 Coo Figs tre is Patent Application Publication Jun. 17, 2010 Sheet 6 of 8 US 2010/0152243 A1 -Ki & .338 p38 tota { 8 x: Ok 3. {x Cie&vex as 888-3 88:33 aaaasssssssssseauxa Figure 6 Patent Application Publication Jun. 17, 2010 Sheet 7 of 8 US 2010/0152243 A1 Patent Application Publication Jun. 17, 2010 Sheet 8 of 8 US 2010/0152243 A1 Control Cels 4 OR incubation 24 OR incubation Figure 8 US 2010/0152243 A1 Jun. 17, 2010 TREATMENT OF RENAL CELL 0007 Stage II: The tumor is larger than 7.0 cm but still CARCINOMA limited to the kidney. There is no spread to lymph nodes or distant organs. CROSS-REFERENCE TO RELATED 0008 Stage III: Includes tumors of any size, with or with APPLICATIONS out spread to fatty tissue around the kidney, with or without spread into the large veins leading from the kidney to the 0001. This application claims priority from U.S. provi heart, with spread to one nearby lymph node, but without sional application Ser. No. 61/195.312 filed Oct. 6, 2008. spread to distant lymph nodes or other organs. Stage III also includes tumors with spread to fatty tissue around the kidney FIELD OF THE INVENTION and/or spread into the large veins leading from the kidney to the heart, that have not spread to any lymph nodes or other 0002 The present invention relates generally to cancer Organs. treatment. More specifically this invention relates to the use 0009 Stage IV: This stage includes any cancers that have of 3,3',4,4-tetrahydroxy-2,2'-bipyridine-N,N-dioxides, espe spread directly through the fatty tissue and the fascia liga cially 3,3',4,4-tetrahydroxy-2,2'-bipyridine-N,N'-dioxide ment-like tissue that surrounds the kidney. Stage 1V also (Orellanine), for the treatment of renal cancer, particularly includes any cancer that has spread to more than one lymph renal cell carcinoma originating from renal proximal tubular node near the kidney, to any lymph node not near the kidney, cells. or to any other organs such as the lungs, bone, or brain. 0010 Detailed definitions of renal cell cancer, T. N. M. BACKGROUND OF THE INVENTION categories, and stage groupings: (0011 Primary Tumor (T): 0003 Cancer appears in more than 100 different forms 0012 TX: Primary tumor cannot be assessed that affect nearly every part of the body. Throughout life, (0013 T0: No evidence of primary tumor healthy cells in the body divide, grow, and replace themselves 0014 T1: Tumor 7 cm or less, limited to kidney in a controlled fashion. Cancer results when the genes dictat 0015 T2: Tumor greater than 7 cm, limited to kidney ing this cellular division malfunction and cells begin to mul 0016 T3: Tumor extends into major veins/adrenal/peri tiply and grow out of control. A mass or clump of these nephric tissue; not beyond Gerota’s fascia abnormal cells is called a tumor. Not all tumors are cancerous. 0017 T3a; Tumor invades adrenal/perinephric fat Benign tumors, such as moles, stop growing and do not 0018 T3b. Tumor extends into renal vein(s) or vena cava spread to other parts of the body. Cancerous or malignant below diaphragm tumors, however, continue to grow and Smother healthy cells, 0019 T3c: Tumor extends into vena cava above dia interfere with body functions, and draw nutrients away from phragm body tissues. Malignant tumors can spread to other parts of 0020 T4: Tumor invades beyond Gerota’s fascia the body through a process called metastasis. Cells from the 0021 N. Regional Lymph Nodes “mother tumor detach, migrate via the blood or lymphatic 0022 NX: Regional nodes cannot be assessed vessels or within the chest, abdomen or pelvis, depending on 0023 NO: No regional lymph node metastasis the tumor, and they eventually form new tumors elsewhere in 0024 N1: Metastasis in a single regional lymph node the body. 0025 N2: Metastasis in more than one regional lymph 0004 Cancer in the kidney constitutes about 3% of all node solid tumors. About 85% of renal tumors are classified as 0026 M Distant Metastasis renal cell carcinoma (RCC) Approximately 80% of diag 0027 MX: Distant metastasis cannot be assessed nosed RCC originate from the epithelial cells lining the proxi 0028 MO: No distant metastasis mal parts of the kidneysurine-forming ducts, the tubuli. Due 0029 M1: Distant metastasis to its appearance under the microscope, this cancer type is 0030. As a rule of thumb, cancer in stage I or II is treated known as either renal clear cell carcinoma (RCCC, 65%) or by Surgical removal of the afflicted kidney and the prognosis renal papillary cell carcinoma (RPCC, 15%). While RCCC for recovery is good. In contrast, renal cancers of stage III or and RPCC constitute 80% of diagnosed RCC, they are IV are associated with very low survival rates, and the responsible for closer to 100% of the deaths from renal cell National Cancer Institute states on its website that "Virtually carcinoma. no patients with renal cell cancer in stage 1 V can be cured 0005. The most important factor in predicting prognosis is 0031. The National Cancer Institute estimates 49,096 new the stage. The stage describes the cancer's size and how cases of renal cancer to be diagnosed in the U.S. in 2009 deeply it has spread beyond the kidney. The Staging System (16/10 citizens) with 11,033 ensuing deaths (3.6/10 citi of the American Joint Committee on Cancer (AJCC) is known Zens). the corresponding numbers for the European Union as the TNM system. The letter T followed by a number from (2006) are 65,051 diagnoses (7.8/10 citizens) and 27.326 1 to 3 describes the tumor's size and spread to nearby tissues. deaths (3.3/10 citizens) (European Cancer Observatory: Higher T numbers indicate a larger tumor and/or more exten http://eu-canceriarc.fr/cancer-19-kidney.htmlen). World sive spread to tissues near the kidney. The letter N followed by wide estimates (2006) are 209,000 diagnosed cases (3.2/10 a number from 0 to 2 indicates whether the cancer has spread citizens) and 102,000 deaths (1.6/10 citizens) (Gupta et al. to lymph nodes near the kidney and, if so, how many are Cancer Treat. Rev. 34, 193-205; 2008). The seemingly higher affected. The letter M followed by a 0 or 1 indicates whether incidence in the U.S. is due to the fact that the NCI co-reports or not the cancer has spread to distant organs. cancer of the renal pelvis (which is relatively easy to treat) 0006 Stage I: The tumor is 7 cm (about 2% inches) or with renal cell carcinomas. The lower global incidence and smaller, and limited to the kidney. There is no spread to lymph death rates are likely due, at least in part, to under diagnosis in nodes or distant organs. large areas of the Third World. US 2010/0152243 A1 Jun. 17, 2010 0032. The main problem with conventional art is that, as cytotoxic agents due to the targeting afforded by the antibody mentioned above, the outcome for any one patient diagnosed (aka the “magic bullet” concept). A similar strategy, based on with renal cancer is dictated largely by the timing of the different tumor-associated antigens, is adopted in diagnosis. If the disease is diagnosed before the tumor has CN1359.941. spread outside the kidney the chance for Survival is good, 0038 U.S. Pat. No. 6,403,373 discloses nucleic acid mol otherwise most patients die from the disease. The main reason ecules associated with colon, renal and stomach cancer, the for this is that renal cell carcinoma is refractory to all conven peptide products of which gives rise to antibody production in tional therapy with cytostatic and/or cytotoxic drugs, such as a host. Use of the peptides in a vaccine approach is contem cisplatin, carboplatin, docetaxel, paclitaxel, fluorouracil, plated. EPO160250 discloses monoclonal antibodies for the capecitabine, gemcitabine, irinotecan, topotecan, etoposide, diagnosis of renal carcinoma, and mentions the possibility of mitomycin, gefitinib, Vincristine, vinblastine, doxorubicin, conjugating these to various cytotoxic agents.
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