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siRNA/shRNA Therapy for the Sensitization of Treatment-resistant Solid Tumors to Chemo and Radiation Therapy

Published:
Lead Inventor: Ralph Weichselbaum
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SUMMARY

  • Adjuvant radiation therapy post-surgery remains largely ineffective, with just 5% of patients showing a survival benefit. Small molecule JAK inhibitors have shown efficacy in the clinic at treating these patients, yet problematically this approach is plagued by off-target toxicities and eventual development of treatment resistance.
  • The inventors used an siRNA screen of 89 different genes downstream of the JAK/STAT pathway in 14 different cancer cell lines to identify specific genes responsible for radiation resistance in tumors. They identified a panel of interferon (IFN)-stimulated genes that confers radiation resistance to cancer cells.
  • The invention is an siRNA/shRNA therapy for the sensitization of radiotherapy resistant tumors. The therapy targets specific genes downstream of the JAK/STAT pathway and therefore has improved specificity over current small molecule JAK inhibitors.
  • The genes were validated using siRNA knockdowns in various cancer cell lines including: colon cancer, breast cancer, glioblastoma, and radioresistant prostate cancer. All cell lines showed increased sensitivity to 5Gy of radiation with knockdown of select genes as compared to untreated.

 

 

FIGURE

Figure 2 LGP2 inhibiting siRNA (siLGP2) increased cell death in three cancer cell lines (D54, WiDr, Scc61) when combined with 5 Gy radiation as compared to irrelevant siRNA (siNT) and radiation alone. LGP2 mediates resistance to radiation by shutting off synthesis of interferon (IFN) and blocking its cytotoxic effects. LGP2 was one of the candidate genes identified in the 89 gene screen.

 

 

ADVANTAGES

ADVANTAGES

  • Novel targets for cancer treatment
  • Boosts efficacy of radiation therapy
  • More targeted and specific than current JAK inhibitors  

 

APPLICATIONS

  • Cancer combination therapy
  • Radiosensitizer
  • Gene Therapy (compatible with RNA delivery platforms)

 

PUBLICATIONS

 

 

 

 

 

 

  • US: 9,790,504
  • US Patent Pending: 16/179,577