Synthetic metabolic lethality in pancreatic cancer.
Mito Laboratories is developing a biomarker-defined strategy in pancreatic ductal adenocarcinoma (PDAC). We focus on glycolytic tumors with elevated LDHA and PDK1 expression, where simultaneous disruption of metabolic flux and anti-apoptotic signaling may produce non-linear, tumor-selective cell death.
Thesis
PDAC tumors frequently survive within hypoxic, nutrient-constrained microenvironments and adapt via high glycolytic flux, elevated lactate production, and suppression of mitochondrial oxidative entry points. These adaptations are often coupled to robust apoptotic resistance.
Mito Laboratories is built on the hypothesis that a defined metabolic subtype of PDAC — glycolytic tumors with elevated lactate dehydrogenase (LDHA) and pyruvate dehydrogenase kinase 1 (PDK1) — can be targeted through coordinated disruption of metabolic flux and apoptosis buffering.
Biomarker-defined selection
Focus on glycolytic PDAC tumors with elevated LDHA and PDK1 expression to define a vulnerable patient subset.
Mitochondria-integrated mechanism
Mitochondria sit at the intersection of metabolic flux, redox balance, and apoptosis execution — enabling high-leverage control.
Non-linear cell fate
The goal is synthetic metabolic lethality: combination effects that exceed additivity and selectively collapse tumor survival.
Mechanism of action (conceptual)
Our lead program is designed around simultaneous inhibition of three integrated modules in LDHA-high / PDK1-high PDAC:
LDH inhibition
Constrains glycolytic throughput and redox recycling by limiting lactate production and associated NADH/NAD+ cycling.
PDK1 inhibition
Shifts pyruvate flux toward mitochondrial oxidation by reducing PDK-mediated suppression of pyruvate dehydrogenase activity.
Pan–Bcl-2 family inhibition
Releases anti-apoptotic buffering at the mitochondria, enabling apoptotic execution under metabolic stress.
In this framework, dual metabolic inhibition is intended to force oxidative flux and elevate mitochondrial stress (e.g., reactive oxygen species and loss of membrane potential) in glycolytic tumors. Under such stress, survival becomes increasingly dependent on anti-apoptotic Bcl-2 family signaling. Concurrent inhibition is designed to trigger mitochondrial outer membrane permeabilization (MOMP) and caspase-mediated apoptosis.
Why dose-sparing matters
Pan–anti-apoptotic Bcl-2 family inhibition can be limited by tolerability. A key objective of our approach is to use metabolic disruption to sensitise tumor cells, reducing the exposure required for apoptotic activation. This dose-sparing hypothesis is central to program design and is measured explicitly in our validation plan.
Goal
Achieve meaningful apoptotic activation at reduced BH3 mimetic exposure in the biomarker-defined PDAC subtype.
How we measure
Formal synergy scoring (e.g., Bliss/Loewe) plus mechanistic readouts (ROS, membrane potential, caspase activation).
Why it’s differentiating
A subtype-selective, dose-sparing profile supports both clinical translation strategy and IP defensibility.
Preclinical validation principles
We design experiments to generate decision-quality data early. The key elements of our validation approach include:
- Subtype stratification: compare LDHA-high / PDK1-high PDAC models to lower-expression controls.
- Synergy quantification: evaluate single, double, and triple combinations with formal synergy scoring.
- Mechanistic causality: confirm mitochondrial stress and apoptotic execution (e.g., ROS dependence and MOMP/caspase activation).
- Translational readouts: establish practical biomarker and pharmacodynamic readouts aligned to mechanism.
From thesis to assets
Mito Laboratories is pursuing a staged path from platform validation to proprietary asset creation:
Layer 1 — Platform IP
Biomarker-defined simultaneous triple inhibition in LDHA-high / PDK1-high PDAC, including mechanistic and dose-sparing claims.
Layer 2 — Proprietary chemistry
Staged inhibitor discovery and optimisation programs targeting LDH, PDK1, and pan–Bcl-2 family modules.
Layer 3 — Translation
Model-informed in vivo validation and development planning aligned to biomarker selection and early clinical signal detection.
We communicate our science responsibly: programs are hypothesis-driven and milestone-gated, with claims anchored to measurable validation and a clear translational plan.