Science
Hypoxia is a major driver of immune suppression and cancer progression
Tumor hypoxia
Tumor hypoxia is a consequence of the aberrant nature of neovasculature in a growing tumor. Some areas of the tumor will experience chronic hypoxia and undergo necrosis, while cells in other areas will experience much more dynamic exposure to oxygen and adapt to these harsh conditions. Hypoxia-adapted cells are resistant towards radio-, chemo-, and immunotherapy and drive metastasis of cancers.
The Achilles Heel of cellular adaption to hypoxia
The lack of oxygen exerts immense strain onto cancer cells in rapid proliferation requiring them to adapt into a slow dividing and stem-like cell state.
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Part of this change happens in the electron transport chain in hypoxic mitochondria. Hypoxic cancer cells lack the oxygen needed for normal electron transport, which forces electrons to build up in the mitochondrial membranes.
Ultimately, this transforms the mitochondrial membranes into a highly electron rich environment. Our proprietary first-in-class drug candidate PH1154 can unleash these electrons and allow them to spread as toxic radicals.
Figure adapted from Spinelli et al., Fumarate is a terminal electron acceptor in the mammalian electron transport chain. Science 374, 1227-1237 (2021). DOI: 10.1126/science.abi7495
Tumor hypoxia empowers an immunosuppressive tumor microenvironment
Tumor hypoxia turns solid tumors "cold" by engaging several immunosuppressive pathways e.g., activation of adenosinergic signalling, recruitment of tumor-associated macrophages, myeloid-derived suppressor cells, and regulatory T-cells.
Consequently, immune checkpoint inhibitors and CAR-T therapies lack efficacy in solid tumors.
By eliminating hypoxic cancer cells, Kripthonite's drug candidate prime solid tumors for immuno-oncology treatments.
PH1154 is a potent and highly selective hypoxia-targeting anticancer agent
As a proof-of-concept, we tested PH1154 in combination with radiation therapy in a hard-to-treat pancreas cancer model.
In this study, 8 out of 8 mice experienced complete regression rendering 4 of these mice tumor-free.
The radiation arm lacked efficacy due to the treatment resistant hypoxic fraction of cancer cells.
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This study highlights the prerequisite of elimination of hypoxic cancer cells for gaining the full potential of immunotherapy or radiation.