Treatment of cancer by inhibiting activity or expression of late SV-40 factor
Patent Number: US9283244
Executive Summary:
General Description:
LSF is highly expressed in HCC tumors. The proof-of-concept that LSF is a good therapeutic target was made. Moreover, LSF has diagnostic and prognostic value as it is associated with high grade tumors.
Scientific Progress:
siRNA-mediated inhibition of LSF sensitizes HCC cells to 5-fluorouracil in mouse xenograft model. Two lead compounds – factor quinolone inhibitor 1 and 2 (FQI1 and FQI2) – that inhibit LSF showed anti-tumor activity as single agents in an endogenous mouse model of HCC. Moreover, LSF is overexpressed in ~90% of human HCC patients and its expression level is correlated with the stages and grades of the disease.
Future Directions:
Strengths:
Weaknesses:
Patent Status:
Legal Status: Active, expires 2031.12.22
Publication PMID: 26313006, 22396589, 22167195, 22679558, 21703197, 20404171, 19622726
Publications:
Rajasekaran D, Siddiq A, Willoughby JL, Biagi JM, Christadore LM, Yunes SA, Gredler R, Jariwala N, Robertson CL, Akiel MA, Shen XN, Subler MA, Windle JJ, Schaus SE, Fisher PB, Hansen U, Sarkar D. Small molecule inhibitors of Late SV40 Factor (LSF) abrogate hepatocellular carcinoma (HCC): Evaluation using an endogenous HCC model. Oncotarget. 2015 Sep 22;6(28):26266-77. doi: 10.18632/oncotarget.4656.
Grant TJ, Bishop JA, Christadore LM, Barot G, Chin HG, Woodson S, Kavouris J, Siddiq A, Gredler R, Shen XN, Sherman J, Meehan T, Fitzgerald K, Pradhan S, Briggs LA, Andrews WH, Sarkar D, Schaus SE, Hansen U. Antiproliferative small-molecule inhibitors of transcription factor LSF reveal oncogene addiction to LSF in hepatocellular carcinoma. Proc Natl Acad Sci U S A. 2012 Mar 20;109(12):4503-8. doi: 10.1073/pnas.1121601109. Epub 2012 Mar 6.
Santhekadur PK, Gredler R, Chen D, Siddiq A, Shen XN, Das SK, Emdad L, Fisher PB, Sarkar D. Late SV40 factor (LSF) enhances angiogenesis by transcriptionally up-regulating matrix metalloproteinase-9 (MMP-9). J Biol Chem. 2012 Jan 27;287(5):3425-32. doi: 10.1074/jbc.M111.298976. Epub 2011 Dec 13.
Santhekadur PK, Rajasekaran D, Siddiq A, Gredler R, Chen D, Schaus SE, Hansen U, Fisher PB, Sarkar D. The transcription factor LSF: a novel oncogene for hepatocellular carcinoma. Am J Cancer Res. 2012;2(3):269-85. Epub 2012 Apr 21.
Yoo BK, Gredler R, Chen D, Santhekadur PK, Fisher PB, Sarkar D. c-Met activation through a novel pathway involving osteopontin mediates oncogenesis by the transcription factor LSF. J Hepatol. 2011 Dec;55(6):1317-24. doi: 10.1016/j.jhep.2011.02.036. Epub 2011 Apr 13.
Yoo BK, Emdad L, Gredler R, Fuller C, Dumur CI, Jones KH, Jackson-Cook C, Su ZZ, Chen D, Saxena UH, Hansen U, Fisher PB, Sarkar D. Transcription factor Late SV40 Factor (LSF) functions as an oncogene in hepatocellular carcinoma. Proc Natl Acad Sci U S A. 2010 May 4;107(18):8357-62. doi: 10.1073/pnas.1000374107. Epub 2010 Apr 19.
Yoo BK, Gredler R, Vozhilla N, Su ZZ, Chen D, Forcier T, Shah K, Saxena U, Hansen U, Fisher PB, Sarkar D. Identification of genes conferring resistance to 5-fluorouracil. Proc Natl Acad Sci U S A. 2009 Aug 4;106(31):12938-43. doi: 10.1073/pnas.0901451106. Epub 2009 Jul 21.
Inventor Bio: Devanand Sarkar
http://www.medschool.vcu.edu/expertise/detail.html?ID=1284
Executive Summary:
- Invention Type: Prognostic/Diagnostic/Therapeutic
- Patent Status: US Grant
- Patent Link: https://patents.google.com/patent/US9283244/
- Research Institute: Virginia Commonwealth University
- Disease Focus: Hepatocellular carcinoma (HCC)
- Basis of Invention: Late SV40 factor (LSF) is highly expressed in HCC patients and promotes oncogenesis in vivo
- How it works: The invention provides methods of treating HCC by the inhibition of LSF, as well as methods of using LSF as a diagnostic and prognostic biomarker
- Lead Challenge Inventor: Devanand Sarkar
- Inventors: Paul B. Fisher, Devanand Sarkar
- Development Stage: Lead optimization (in vivo) + human data for the biomarker
- Novelty:
- Novel therapeutic target for the treatment of HCC
- Novel diagnostic/prognostic biomarker
- Clinical Applications:
- Treatment of HCC
- Diagnostic and prognostic biomarker
General Description:
LSF is highly expressed in HCC tumors. The proof-of-concept that LSF is a good therapeutic target was made. Moreover, LSF has diagnostic and prognostic value as it is associated with high grade tumors.
Scientific Progress:
siRNA-mediated inhibition of LSF sensitizes HCC cells to 5-fluorouracil in mouse xenograft model. Two lead compounds – factor quinolone inhibitor 1 and 2 (FQI1 and FQI2) – that inhibit LSF showed anti-tumor activity as single agents in an endogenous mouse model of HCC. Moreover, LSF is overexpressed in ~90% of human HCC patients and its expression level is correlated with the stages and grades of the disease.
Future Directions:
- Clinical development
Strengths:
- Therapeutic, diagnostic and prognostic value
- First-in-class drugs
Weaknesses:
- Other treatment of HCC
Patent Status:
Legal Status: Active, expires 2031.12.22
- Priority date: 2010.04.01
- Filing date: 2011.03.29
- Publication date: 2016.03.15
- Grant date: 2016.03.15
Publication PMID: 26313006, 22396589, 22167195, 22679558, 21703197, 20404171, 19622726
Publications:
Rajasekaran D, Siddiq A, Willoughby JL, Biagi JM, Christadore LM, Yunes SA, Gredler R, Jariwala N, Robertson CL, Akiel MA, Shen XN, Subler MA, Windle JJ, Schaus SE, Fisher PB, Hansen U, Sarkar D. Small molecule inhibitors of Late SV40 Factor (LSF) abrogate hepatocellular carcinoma (HCC): Evaluation using an endogenous HCC model. Oncotarget. 2015 Sep 22;6(28):26266-77. doi: 10.18632/oncotarget.4656.
Grant TJ, Bishop JA, Christadore LM, Barot G, Chin HG, Woodson S, Kavouris J, Siddiq A, Gredler R, Shen XN, Sherman J, Meehan T, Fitzgerald K, Pradhan S, Briggs LA, Andrews WH, Sarkar D, Schaus SE, Hansen U. Antiproliferative small-molecule inhibitors of transcription factor LSF reveal oncogene addiction to LSF in hepatocellular carcinoma. Proc Natl Acad Sci U S A. 2012 Mar 20;109(12):4503-8. doi: 10.1073/pnas.1121601109. Epub 2012 Mar 6.
Santhekadur PK, Gredler R, Chen D, Siddiq A, Shen XN, Das SK, Emdad L, Fisher PB, Sarkar D. Late SV40 factor (LSF) enhances angiogenesis by transcriptionally up-regulating matrix metalloproteinase-9 (MMP-9). J Biol Chem. 2012 Jan 27;287(5):3425-32. doi: 10.1074/jbc.M111.298976. Epub 2011 Dec 13.
Santhekadur PK, Rajasekaran D, Siddiq A, Gredler R, Chen D, Schaus SE, Hansen U, Fisher PB, Sarkar D. The transcription factor LSF: a novel oncogene for hepatocellular carcinoma. Am J Cancer Res. 2012;2(3):269-85. Epub 2012 Apr 21.
Yoo BK, Gredler R, Chen D, Santhekadur PK, Fisher PB, Sarkar D. c-Met activation through a novel pathway involving osteopontin mediates oncogenesis by the transcription factor LSF. J Hepatol. 2011 Dec;55(6):1317-24. doi: 10.1016/j.jhep.2011.02.036. Epub 2011 Apr 13.
Yoo BK, Emdad L, Gredler R, Fuller C, Dumur CI, Jones KH, Jackson-Cook C, Su ZZ, Chen D, Saxena UH, Hansen U, Fisher PB, Sarkar D. Transcription factor Late SV40 Factor (LSF) functions as an oncogene in hepatocellular carcinoma. Proc Natl Acad Sci U S A. 2010 May 4;107(18):8357-62. doi: 10.1073/pnas.1000374107. Epub 2010 Apr 19.
Yoo BK, Gredler R, Vozhilla N, Su ZZ, Chen D, Forcier T, Shah K, Saxena U, Hansen U, Fisher PB, Sarkar D. Identification of genes conferring resistance to 5-fluorouracil. Proc Natl Acad Sci U S A. 2009 Aug 4;106(31):12938-43. doi: 10.1073/pnas.0901451106. Epub 2009 Jul 21.
Inventor Bio: Devanand Sarkar
http://www.medschool.vcu.edu/expertise/detail.html?ID=1284