Kinase inhibitors & cancer - Potentiating anti-PD1 antitumor immunotherapy

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21 Septembre 2016

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Fields

Chemistry Biology / Medical

Sectors

Health

BACKGROUND

Immune-checkpoint blockades targeting CTLA-4, PD1, PDL-1 are major breakthroughs in cancer therapy, increasing overall survival. The launch of these premium-priced metastatic immunotherapies will extend treatment duration and replace cheaper, generic, chemotherapy regimens.

But still, too few patients respond to these therapies: 10% to 57% depending on the cancer type and the treatment combinations.

HOW IT WORKS

A team of chemists and biologist physicians demonstrated that the inhibition of the non-canonical NF-kappa-B pathway by DMPB5, a new multi-kinase inhibitor:

  • Restores in vitro a strong senescence in melanoma (not dependent of the mutations), colon, lung and breast cells by decreasing the transcription of EZH2, a key oncogene.
  • Triggers or potentiates in vitro and in vivo the tumor immune surveillance: increases production of a cytokine that attracts immune cells (macrophages M1, dendritic cells, T-cells and NK cells).
  • Leads to a dramatic reduction in tumor size with complete regression in some cases when combined with anti-PD-1 treatments.

KEY BENEFITS vs. STATE OF THE ART

  • An effective kinase inhibitor (DMPB5) working at 10 mg/kg every other day compared to 30 to 100 mg/kg one or twice a day for most molecules tested in mouse model
  • DMBP5 reduces tumor growth directly, but also potentiates anti-PD1 treatments
  • No clinical signs of preliminary toxicity in mice treated with DMBP5

DEVELOPMENT STATUS

In vitro: high potencyon melanoma cells, metastatic melanoma primary cells from patient, non-small cell lung cancer and colorectal cancer cells

In vivo activity at 10mg/kg, i.p., on colorectal cancer cells injected subcutaneously into syngeneic mice; greater activity for combination DMBP5/PD-1 (Figure)

Ongoing hit-to-lead and lead optimization, target validation and non-regulatory preclinical validation on melanoma tumors and metastases mouse models

APPLICATIONS

Melanoma and metastatic melanoma (B-Raf mutated and wild type)

Solid tumors including colorectal, prostate, pancreatic and lung (NSCLC) cancers

 

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