Scientific Background and Clinical Relevance of the NOTCH Pathway
The NOTCH pathway is one of the pivotal cell-to-cell communication mechanisms in developed organisms and is highly conserved across species from fruit flies (drosophila) to human.
Aberrant activation of the NOTCH pathway due to genetic lesions, leads to oncogenic transformation of normal cells and causes NOTCH driven human cancers. Over 250´000 patients are annually diagnosed with NOTCH dependent cancers, with no specific therapy available to date.
In recent clinical investigations, NOTCH activation has been confirmed to be an important negative prognostic factor across multiple cancer indications, e.g. breast cancer, leukemias and several subtypes of lymphomas. Patients “positive” for NOTCH have a significantly reduced chance of survival.
With no targeted therapies available yet, NOTCH activated cancers kill patients faster, and for those patients, inhibition of NOTCH signalling is expected to give a substantial survival benefit, by blockade of a key oncogenic driver.
Importantly, as shown above the NOTCH signalling pathway is confirmed as a clinically relevant and validated oncology therapeutic target: Disease control has been achieved in individual cancer patients receiving NOTCH inhibitors in ongoing clinical trials, hence clinical “proof of concept” with this approach has been demonstrated. However, therapeutic antibodies in development specifically block only selected sub-sets of NOTCH receptors/ligands interactions. I On the other hand, inhibitors of the gamma-secretase enzyme, target the pathway at the level of the membrane of tumor cells, and therefore cannot inhibit receptors/ligands independent intracellular NOTCH constitutive activation, caused by genetic lesions like chromosomal translocations. Moreover, the gamma-secretase enzyme is not solely dedicated to regulation of the NOTCH pathway, and also cleaves more than 80 additional membrane-bound protein substrates, suggesting that inhibition of the gamma-secretase enzyme will lead to numerous NOTCH independent effects.
In contrast, CB-103 is acting at the most downstream part of the pathway, in the cell nucleus, by binding to the NOTCH transcription complex, thereby centrally inhibiting NOTCH activation for all NOTCH receptors. With this unique and novel mode of action, CB-103 allows the inhibition of the NOTCH pathway regardless of the cause of NOTCH activation.
Cellestia Biotech is therefore confident that CB-103, targeting the central and terminal point of the NOTCH activation pathway, is going to demonstrate clinical efficacy in patients, and in particular able to reach a larger patient population, compared to competitors, due to this novel mode of action.