Mechanism of Action
Tyme’s Mechanism of Action and Platform Overview
SM-88 is Designed to Target Only Active Cancer Cells.
Chemotherapy compounds are toxic, and are designed to interfere with the mechanism of cell division but are not selective, and thus toxic to the organs and the body as a whole. Unlike many toxic chemotherapies, SM-88 is designed to target only active cancer cells and to force them to be vulnerable to the body’s natural defenses and processes.
We believe SM-88’s mechanism of action (“MOA”) can be broadly effective across different cancer types because it has a unique composition. It is designed to selectively invade a cancer cell, weaken its defenses, and to expose its microenvironment to oxidative stress and to host immune system defenses, regardless of a tumor’s origin.
SM-88, including our proprietary tyrosine derivative compound, is designed to be selective to tumors with minimal impact on normal healthy cells. We believe our research, as well as independent studies, suggest that cancer cells have a high affinity for tyrosine, especially in a glucose-deprived or cellular ketosis state. Normal cells have less affinity to tyrosine and do not significantly use tyrosine as a metabolite.
Our product development strategy is based on using “biological circuits” to selectively destroy tumor cells with minimal toxicity. In this regard, the term biological circuit is meant to describe a cascading process of cellular function when a cancer cell is in its natural state. SM-88 is designed to increase the “current” of this circuit and then cause a break at a critical juncture to induce a catastrophic collapse of the cancer cell. We believe this can be a highly effective strategy against cancer since all cancers have an altered glycolytic metabolism, involving glucose breakdown, known as the Warburg Effect.
SM-88 is designed as a therapeutic treatment to utilize a cancer cell’s glycolytic process to create a potential universal entry point for producing cancer cell death through oxidative stress and the body’s immune system defenses.
The backbone component of SM-88 is a proprietary dysfunctional tyrosine derivative. Tyrosine is a non-essential amino acid that has a high affinity with cancer cells, but has minimal uptake by healthy cells. The tyrosine derivative used in SM-88 is designed to interact with the cancer cell as if it were a functional tyrosine. After uptake, SM-88’s dysfunctional tyrosine causes any cellular process using the tyrosine derivative, such as protein synthesis, to fail.
One of the critical proteins in cancer that uses tyrosine as an important building block is mucin and is produced by the oncogene MUC1. Mucin acts as a protective layer around the cancer cell that defends the tumor from external elements, such as the host immune system, and also helps maintain a stable balance inside of the cancer cell. Cancers have an internal microenvironment that would be toxic to healthy cells and we believe mucins help keep the microenvironment in a state of balance. SM-88 is intended to disrupt the cancer cell’s unique microenvironment following uptake of our tyrosine derivative.
We hypothesize that when the cancer cell attempts to use the dysfunctional tyrosine derivative for protein synthesis to create mucin, the process fails and the mucin layer begins to deteriorate. Without a stable protective coating from mucin, tumor cells become exposed to the host immune system as well as internal toxicity. This can result in a heightened state of oxidative stress, when the number of free-radicals or reactive oxygen species (“ROS”) increases to a dangerous level. ROS can cause catastrophic cancer cell damage, leading to apoptosis, by pulling electrons from otherwise stable molecules, such as DNA or proteins.
Tyme believes the effectiveness of our tyrosine derivative in inducing cancer cell death is substantially enhanced by combining it with small doses of three repurposed agents that may increase the uptake of the tyrosine derivative and enhance oxidative stress against the tumor cells.
One repurposed agent, sirolimus, is administered with the intent to increase the rate at which a cell exhausts its supply of glucose and, as a result, must use amino acids and lipids for metabolism. We believe that by decreasing glucose supply with sirolimus, cancer cells will more quickly exhaust their glucose supply and begin pulling in preferred amino acids, such as tyrosine. Because it is estimated that cancer cells utilize glucose at less than 1/15th the efficiency of normal cells, cancer cells are expected to deplete their glucose far more rapidly than normal cells, causing a dramatic increase in tyrosine uptake, including SM-88’s tyrosine derivative.
The other two repurposed agents, methoxsalen and phenytoin, are administered to increase the oxidative stress on cancer cells. We believe that phenytoin can stimulate the production of reactive lipid species and increase the overall level of oxidation surrounding a cancer cell. We believe that methoxsalen can promote an electron transfer process and enhance the effect of ROS and the ability to catalyze oxygen into the cancer cell, which produces cell death within the cancer cell microenvironment.
All three of these repurposed agents are administered at doses that are approximately 25% or less than their recommended therapeutic dosing levels. We believe that small doses of these repurposed agents should have too little of an effect to cause disruption of normal cellular function, but in combination should meaningfully increase the effectiveness of SM-88 therapy against cancer.
By using SM-88 to disrupt cancer’s metabolic circuit, our intention is to create a therapy that is:
- Broadly effective across different cancer types – Since all cancers use the same metabolic process, they also have the same potential entry point for therapy, regardless of origin;
- Highly specific to cancer – As supported by recent advances in radiographic imaging that use tyrosine to selectively image cancer cells, cancer has a high affinity for tyrosine while normal cells have minimal uptake;
- Relatively non-toxic – Studies in relatively healthy individuals have not shown significant side effects;
- An effective treatment for patients who have failed other therapeutic options – Due to it’s a novel MOA and low toxicity profile, we believe SM-88 can be an effective alternative to existing standard of care treatments that have failed and many previous therapies should not produce enhanced resistance to SM-88.
- Suitable for monotherapy or combination therapy – Although most of Tyme’s clinical and compassionate use experience has been in monotherapy, SM-88’s differentiated MOA and safety profile could allow it to be effective in combination with other cancer therapeutics; and
- Less likely to create cancer resistance – By taking advantage of cancer’s natural state rather than trying to target specific mutations, cancer may have less ability to find alternate pathways to function.