Endo-205, Lesion Metabolism, and the Survival-Pocket Question — Part 2

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Full transcript of the original video, lightly edited for readability.

That means different regions of the same lesion may behave differently some areas may be hypoxic and glycolytic some areas may be oxygenated and mitochondrial some cells may rely more on anaerobic glycolysis other cells may shift toward oxidative phosphorylation or oxfos and some lesions may contain a mixture of both this matters because if Endo-205 depends on acidic pH to unlock its cell penetrating behavior then not every region of a lesion may activate Endo-205 equally. Let me explain that inside a lesion you may have a hypoxic core that core may be poorly vascularized it may not receive enough oxygen so those cells rely heavily on glycolysis they produce lactate they acidify the local environment.

That is the kind of area Endo-205 is theoretically built to recognize but the edge of the lesion may behave differently especially in active vascularized red lesions the outer region may have more oxygen availability those cells may use oxidative phosphorylation to generate ATP more efficiently they may still be disease they may still be invasive they may still have broken WNT beta catenin signaling they may still be contributing to fibrosis tissue remodeling and survival but if they are not creating the same acidic microenvironment Endo-205 may not enter them as efficiently that creates a possible blind spot the drug may be designed to enter acidic cells.

But what happens to the disease cells that are less acidic what happens to the oxphos heavy cells what happens to the metabolically flexible cells what happens to the cells sitting in a more neutral pH zone but still carrying the abnormal intracellular machinery that drives disease. That is the concern because. The second mechanism beta catenin targeting only matters if Endo-205 gets inside the cell you can have a perfect intracellular target but if the peptide does not unlock at the membrane it never reaches that target.

That is the limitation people need to understand Endo-205's intracellular mechanism may be brilliant but the pH dependent delivery gate could be uneven if the lesion itself is metabolically mixed and endometriosis is very likely metabolically mixed there may even be metabolic cooperation inside the lesion some cells may dump lactate through glycolysis neighboring cells may absorb that lactate and feed it into mitochondrial metabolism. In other words one group of cells may create acidic byproducts while another group uses those byproducts as fuel. That means the lesion is not just a ball of acid it is a metabolic ecosystem a mixed economy a living adaptive tissue environment some cells produce lactate some cells consume lactate some cells are glycolytic some cells are oxidative some cells are hypoxic some cells are vascularized some cells may be acidic enough to trigger end O2O5 some cells may not and this creates what I would call the survival pocket problem if Endo-205 primarily enters the acidic glycolytic pockets of lesion it may damage or clear those regions while leaving behind oxfords driven less acidic pockets and those surviving cells could continue the disease process they could keep proliferating they could keep remodeling tissue they could keep feeding fibrosis they could keep communicating with immune cells they could keep maintaining the lesion architecture and eventually they could become part of the recurrence problem because when a treatment pressures one biological state the cells surviving in the alternate state may be the ones that remain that does not mean Endo-205 cannot work it means the P H selectivity claim needs to be tested against real lesion heterogeneity and may be coupled with the z 1 3 peptide it's not just clean diagrams not just simplified summaries real lesions mixed lesions fibroid lesions deep lesions vascularized lesions ovarian lesions peritoneal lesions post surgical lesions adenomyosis overlap patients because the real question is not simply can Endo-205 enter acidic endometriosis cells the real question is can Endo-205 reach and affect enough of the metabolically diverse lesion to create meaningful clinical clearance.

That is the key now Endo-205 has a second layer. This is where beta catenin and the WNT pathway come in the canonical WNT beta catenin pathway is a major pathway involved in development tissue growth cellular identity adhesion migration survival and remodeling in healthy cells beta catenin is tightly controlled if too much beta catenin builds up in the cytoplasm the cells internal clean up system marks it for degradation that prevents beta catenin from flooding the nucleus and turning on genes that should not be turned on but in endometriosis WNT beta catenin signaling can become over activated the system gets jammed on beta catenin accumulates in the cytoplasm then it translocates into the nucleus once inside the nucleus beta catenin binds t C F and L E F transcription factors that activates genes involved in survival invasion migration fibrosis and tissue remodeling in plain English the lesion becomes harder to kill harder to clear better at invading better at remodeling tissue better at behaving like a wound that refuses to heal Endo-205 is designed to bind cytoplasmic beta catenin.