Title:
BIOMARKERS FOR RESPONSE TO RAPAMYCIN ANALOGS
Document Type and Number:
WIPO Patent Application WO/2014/144451
Kind Code:
A3
Abstract:
The present invention relates to the use of one or more biomarkers to evaluate the likelihood that a rapamycin analog would produce an anti-cancer effect in a subject. It is based, at least in part, on the results of experiments employing an integrated next-generation sequencing approach to interrogate spatially separated tumor specimens from the same individuals to decipher intra-tumor and intertumor heterogeneity and determine the oncogenomic basis of exceptional therapeutic benefit to rapalogs in kidney cancer patients. These experiments implicated loss of function mutations in TSC1 and/or TSC2 and/or gain-of- function of mTOR in therapeutic responsiveness to rapamycin analogs. Accordingly, in non-limiting embodiments, the present invention provides for assay methods and kits for determining the presence of loss of function mutations in TSC1 and/or TSC2 and/or gain-of- function of mTOR, and methods of using such determinations in selecting a therapeutic regimen for a cancer patient and in methods of treating cancer patients. In particular non-limiting embodiments, a plurality of tumor sites are evaluated and the composite effect of the genetic background on mTOR function is assessed.
Inventors:
HSIEH JAMES J (US)
BERGER MICHAEL (US)
MOTZER ROBERT (US)
VOSS MARTIN H (US)
HAKIMI A ARI (US)
PHAM CAN (US)
CHENG EMILY (US)
BRANNON ROSE (US)
XU JIANING (US)
BERGER MICHAEL (US)
MOTZER ROBERT (US)
VOSS MARTIN H (US)
HAKIMI A ARI (US)
PHAM CAN (US)
CHENG EMILY (US)
BRANNON ROSE (US)
XU JIANING (US)
Application Number:
PCT/US2014/028867
Publication Date:
December 31, 2014
Filing Date:
March 14, 2014
Export Citation:
Assignee:
SLOAN KETTERING INST CANCER (US)
International Classes:
C12Q1/68
Foreign References:
| US20120196870A1 | 2012-08-02 | |||
| US20120157340A1 | 2012-06-21 | |||
| US6326483B1 | 2001-12-04 | |||
| US20050070567A1 | 2005-03-31 |
Other References:
KUCEJOVA, B ET AL.: "Interplay Between pVHL And mTORC1 Pathways In Clear- Cell Renal Cell Carcinoma.", MOLECULAR CANCER RESEARCH, vol. 9, no. 9, 28 July 2011 (2011-07-28), pages 1255 - 1265, XP055282981
KOBAYASHI, T ET AL.: "A germ-line Tsc1 mutation causes tumor development and embryonic lethality that are similar, but not identical to, those caused by Tsc2 mutation in mice.", PNAS, vol. 98, no. 15, 17 July 2001 (2001-07-17), pages 8762 - 8767, XP055282984
WANDER, SA ET AL.: "Next-Generation mTOR Inhibitors In Clinical Oncology: How Pathway Complexity Informs Therapeutic Strategy.", THE JOURNAL OF CLINICAL INVESTIGATION, vol. 121, no. 4, 1 April 2011 (2011-04-01), pages 1231 - 1241, XP055282986
IYER, G ET AL.: "Genome Sequencing Identifies A Basis For Everolimus Sensitivity.", SCIENCE, vol. 338, no. 6104, 12 October 2012 (2012-10-12), pages 221, XP055282987
KOBAYASHI, T ET AL.: "A germ-line Tsc1 mutation causes tumor development and embryonic lethality that are similar, but not identical to, those caused by Tsc2 mutation in mice.", PNAS, vol. 98, no. 15, 17 July 2001 (2001-07-17), pages 8762 - 8767, XP055282984
WANDER, SA ET AL.: "Next-Generation mTOR Inhibitors In Clinical Oncology: How Pathway Complexity Informs Therapeutic Strategy.", THE JOURNAL OF CLINICAL INVESTIGATION, vol. 121, no. 4, 1 April 2011 (2011-04-01), pages 1231 - 1241, XP055282986
IYER, G ET AL.: "Genome Sequencing Identifies A Basis For Everolimus Sensitivity.", SCIENCE, vol. 338, no. 6104, 12 October 2012 (2012-10-12), pages 221, XP055282987
Attorney, Agent or Firm:
KOLE, Lisa, B. (30 Rockefeller PlazaNew York, NY, US)
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