The Development of Therapeutics Targeting Both Cancer & Its Microenvironment


tumor microenvironmentTumors are not just lumps of malignant cells growing in isolation.  They create an ecosystem, termed tumor microenvironment, which plays an important role in promoting tumor growth throughout all stages of cancer progression.   Emerging evidence shows that cancer cells influence the microenvironment surrounding the tumor in several ways.  One of the hallmarks is the recruitment cancer associated fibroblasts (CAFs).  Cancer cells then corrupt or transform these cells to an altered metabolic state, secreting nutrients and certain metabolites that favor the growth, invasion, and angiogenesis of the tumor. Hence, an ideal cancer therapy should target not only the cancer itself but also its microenvironment.

Ambryx has discovered several embryonic peptides that induce apoptosis in both cancer cells and CAFs in the tumor microenvironment while leaving normal cells unharmed.   This discovery is an approach inspired by nature’s design.


The Developmental Biology Approach: an elegant & selective design to treat cancer


During embryo development, certain cells are subjected to programmed cell death (apoptosis) induced by factors secreted by embryo (embryo modulators).  This process, known as morphogenesis, is necessary for organ formation.  Cancer cells, on the other hand, has been shown to acquire certain embryo properties including gene expression, metabolism, proliferation, invasion, and angiogenesis—–a phenomenon called “retro-differentiation”.  Inspired by this natural phenomenon, we tested whether the apoptosis-inducing embryo modulators can also induce apoptosis in cancer.  Several embryonic proteins and their peptides have since been discovered to be able to induce apoptosis in both cancer cells and embryonic cells. Interestingly, normal cells are not affected by these embryonic modulators, making them suitable drug candidates for cancer therapy.  This selectivity is due to the fact that adult normal cells which are developmentally mature are not expressing the genes necessary for embryogenesis, therefore are not affected by these embryo modulators.  This technology is termed “Retro-differentiational Cancer Therapy” (R-ACT).


Mechanism of Action


These embryonic modulators effectively accumulate in the mitochondria, inhibiting cancer cell-specific mitochondria-associated hexokinase II, glutaminase, and electron-chain complex I & III. Obstructing multiple mitochondria bioenergetic pathways leads to rapid depletion of ATP and building blocks, resulting in cancer cell death.

Cancer mitochondrial metabolism: Both embryonic and cancer cells share similar metabolic reprogramming.  An example is the high rate of glucose metabolism (Warburg effect) by express high level of mitochondria-associated hexokinase II.  Normal cells which mainly express hexokinase I located in the cytoplasm are not affected by the mitochondria-bound Zn-peptides.     Furthermore, while the electron-chain I & III in cancer cells are inhibited by these peptides, respiratory chains in normal cells are robust and not significantly affected by these peptides.

Increased glutamine metabolism is another hallmark of cancer metabolism.  Many cancer cells are addicted to using glutamine to generate building blocks. Glutaminase is the first enzyme in the glutamine metabolism pathway, and divalent cations (such as Mg2+, Mn2+, Zn2+) has been known to inhibit glutaminase activity.  Our zinc-peptide complex inhibits glutaminase activity in the high nanomolar range.

Targeting tumor microenvironment: Cancer cells are able to transform cancer-associated fibroblasts (CAF) in the tumor microenvironment to be metabolically similar to cancer cells.  CAFs, similar to cancer cells, expresses high level of hexokinase II and performs aerobic glycolysis. Our biochemical study showed that the Zn-peptides also inhibit hexokinase II and causing ATP depletion in CAF, which offers an explanation for the induction of apoptosis in CAFs, albeit with a higher IC50.