Science Delphia Therapeutics

It’s time to approach

cancer biology from a

new perspective.

Breakthrough research has revealed that many oncogenic pathways are also highly vulnerable to overactivation. Too much pathway activation can actually drive lethal cellular stress (“activation lethality”).

Delphia is leveraging activation lethality to develop the next wave of targeted oncology medicines with the potential to deliver durable benefit to patients.

Activation lethality: the undrugged quadrant.

Selective pressures drive tumorigenesis and teach what to drug.
Mutations can be classified by their biological effect and whether the mutation is selected for or against.
To date, our field has focused cancer medicines on the first three quadrants of cancer genetics.
We are pioneering drug discovery in the fourth (undrugged) quadrant – activation lethality.

Selection Pressure

Mutation's
Biological Effects:

Oncogene

Activation
Lethality

Tumor
Suppressor

Synthetic
Lethality

Mutations in oncogenes drive cancer by boosting activity of key pathways that drive cell growth.

Targeted therapies that inhibit oncogenes block pathway activity and lead to an initial response.

But tumors are heterogeneous, and under the selective pressure of inhibitor therapy, resistance rapidly emerges. This pattern is seen again and again across oncology.

At Delphia, we are taking a fundamentally different approach

We are leveraging activation lethality, the suprising new finding that for many pathways, cancers are equally–if not more–vulnerable to overactivation  of these key growth pathways.

Oncogene overactivation leads to an overload on cell stress pathways and is selectively lethal to cancers with mutations that put them close to the upper bounds of tolerable pathway activity.

OUR
APPROACH

Delphia’s three approaches to discovering activation lethal targets

Tumor genetics

Tumor genetics have been the best predictor of successful targets in oncology, and new analytical approaches reveal genetic evidence of activation lethality in multiple critical cancer pathways.

Functional genomics

While CRISPR and shRNA have been widely used for loss-of-function genomic screening, Delphia & our founders are extending functional genomics beyond loss-of-function to gain-of-function, identifying targets that drive activation lethality.

Inhibitor drug resistance (addiction)

Translational research on inhibitor drug resistance shows that some tumors actually regress after the inhibitor is removed, because pathway activity overshoots.

Drugging activation lethality

Many cellular pathways are homeostatic –  the cell adjusts pathway activity to a ‘just right level’ via the activity of positive and negative regulators.

Critical cellular pathways have multiple layers of regulation to ensure the right output activity level oncogenic mutations disrupt this control, boosting pathway activity and disabling much of this regulation. In cells with oncogenic mutations, the remaining regulators are vulnerable – a ‘last line of defense’ from overactivation. At Delphia, we identify these key, vulnerable regulators and drug them, driving overactivation and the selective killing of tumor cells.
We do this via two approaches:

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