Columbia Technology Ventures

Prevention and modulation of chemotherapy resistance in glioblastomas

This technology is a method to delay or reduce temozolomide resistance in glioblastoma cancer patients, and can also be used to treat cancer in subjects with temozolomide resistance by reducing the degree of resistance.

Unmet Need: Method to prevent temozolomide resistance in glioblastoma patients

Current standard treatments for glioblastoma multiforme (GBM) include chemotherapy using the DNA-alkylating agent temozolomide (TMZ) alongside surgical resection and irradiation. However, almost all GBM patients develop gradual resistance to TMZ due to increased expression of a DNA repair enzyme, O6-methylguanine-DNA methyltransferase (MGMT), in TMZ-treated tumor cells. MGMT reduces sensitivity to TMZ by removing the cytotoxic DNA lesions TMZ creates, thus rendering the treatment ineffective.

The Technology: Inhibition of MGMT to prevent temozolomide resistance in glioblastoma patients

This technology identified an enhancer genetic element far from the MGMT gene that increases the expression of both MGMT and Ki67, a well-known marker for cell proliferation that is dysregulated in several cancer lines. The technology found that perturbing this enhancer using epigenetic small molecule drugs such as bromodomain inhibitors (BETi), or histone acetyltransferase inhibitors (HATi), increased the sensitivity of the cancer to TMZ. By combining the use of these agents with TMZ, this technology has been shown to slow tumor TMZ resistance or restore tumor sensitivity to TMZ, and therefore has the potential to improve the efficacy of GBM treatments.

This technology has been validated using patient-derived GBM xenograft cell lines.

Applications:

  • Improved chemotherapeutic treatment of glioblastoma multiforme (GBM)
  • Therapeutic strategy for treatment of other chemotherapy-resistant glioblastoma tumors
  • Development of in vitro and animal models of GBM
  • Research tool to study mechanisms of cancer cell resistance to chemotherapy

Advantages:

  • Identifies therapeutics that modulate the O6-methylguanine-DNA methyltransferase (MGMT) enhancer
  • Restores GBM cell sensitivity to temozolomide (TMZ)
  • May reduce GBM cell proliferation
  • Allows for continued use of TMZ, the most widely used therapeutic agent for GBM
  • Does not cause enhanced hematologic toxicity like other MGMT inhibitor strategies

Lead Inventor:

Zhiguo Zhang, Ph.D.

Patent Information:

Patent Pending (US20210060006)

Related Publications:

Tech Ventures Reference: