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Notch 3 – Inhibitors for the treatment of acute lymphoblastic leukemia

Acute lymphoblastic leukemiaHistone deacetylase inhibitors 6Leukemia treatmentNotch3oncology

Introduction

NOTCH is a signaling pathway frequently altered in some forms of leukemia and in certain solid tumors (e.g. breast and ovarian cancer). NOTCH inhibiting drugs could find therapeutic use in the case of tumors with high NOTCH expression. The drugs used so far are mainly targeted against NOTCH1, rather than NOTCH3.

Technical features

Some NOTCH inhibitors such as monoclonal antibodies and gamma-secretase inhibitors (GSIs) have already been developed and tested in clinical studies, but these drugs have proven to be ineffective and toxic in the intestine. There is therefore a need for new drugs capable of blocking NOTCH3 by mechanisms other than the previous ones.

The patent proposes to use a compound represented by a histone deacetylase 6 (HDAC6) inhibitor for the treatment of neoplasms characterized by mutations or gene amplification of the NOTCH3 gene and / or mutations of the NOTCH1 gene. New mechanism of action: HDAC6 regulates vesicular trafficking and the degradation of NOTCH3 by modulating the acetylation state of tubulin. HDAC6 inhibitors reduce the expression of NOTCH3 and prevent its activation. Some HDAC6 inhibitors have already been used in the clinic and have moderate toxicity.

Possible Applications

  • Tumor forms treatment;
  • Acute T-cell lymphoblastic leukemia treatment (T-5 ALL);
  • Patient with mutations or gene amplification of the NOTCH3 gene;
  • Pediatric patient under the age of 15;
  • Association of the compounds of the invention in with other drugs;
  • In the long term (3-5 years), possible applications concern the development of innovative therapies for a subgroup of acute leukemias and breast and ovarian carcinomas characterized by high levels of expression of NOTCH 3.

Advantages

  • Greater efficacy in the treatment of acute T-cell lymphoblastic leukemia (T-5 ALL);
  • Inhibition of HDAC on cell proliferation and apoptosis;
  • Significant reduction of Notch3 receptor protein levels in all tested cell lines;
  • Reduction of Notch3 levels at the cell membrane level;
  • Inhibition of proliferation and induction of cell death of treated leukemic cells;
  • In the short term (1-3 years) the patent will facilitate collaborations with pharmaceutical companies interested in the development of HDAC6 inhibitors, in order to investigate the activity of their drugs on tumor samples with high NOTCH 3 expression.