On June 22, 2020 Tyme Technologies, Inc. (NASDAQ: TYME), an emerging biotechnology company developing cancer metabolism-based therapies (CMBTs), reported new preclinical findings that describe the unique mechanism of action of its lead cancer metabolism-based candidate, SM-88 (racemetyrosine), that are being presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) 2020 Virtual Meeting from June 22 to June 24, 2020 (Press release, TYME, JUN 22, 2020, View Source [SID1234561337]).
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TYME’s CMBTs are proprietary investigational compounds that leverage cancer’s altered metabolism and associated vulnerabilities to specifically disrupt fundamental cellular processes. This can include altering protein synthesis, increasing oxidative stress, decreasing pH levels, and compromising protein or lipid barriers. In addition, CMBTs may target select survival mechanisms including autophagy, as well as alter the tumor microenvironment to improve immune recognition of the cancer cell.
"These preclinical results advance our understanding of the effect of SM-88 as a standalone oral therapy and begin to describe the mechanisms which underlie the clinical responses observed across multiple tumor types, both solid and liquid," said Jonathan Eckard, Ph.D., Chief Business Officer at TYME. "Key findings suggest that single agent SM-88 increases levels of oxidative stress in cancer cells; interferes with the multifaceted survival mechanism of autophagy; and modulates tumor immunity. These findings begin to highlight the unique profile of SM-88, and the ongoing work will aid in future clinical development of SM-88, both as monotherapy and in combination approaches with existing therapies."
TYME has initiated comprehensive in vitro and in vivo experimental studies that are designed to elucidate the mechanism of action and further characterize the anti-cancer effects of SM-88 as a standalone investigational compound. In a human colon cancer animal model study (HCT-116), the results showed that mice treated with the highest dose of oral SM-88 alone achieved a statistically significant (p < 0.05) reduction in tumor size compared to control-treated mice (n=11 per group). To further validate the anti-cancer effects of SM-88, a second in vivo study was conducted using a pancreatic cancer animal model (PAN02). The data from this study demonstrated that mice treated with intraperitoneally administered with the highest dose of SM-88 alone had a statistically significant tumor reduction compared to those treated with control alone (n=10 per group).
Increasing Reactive Oxygen Species (ROS):
Oxidative stress is the result of elevated levels of reactive oxygen species in cancer cells. Cancer cells are recognized to have elevated ROS levels and attempt to carefully balance these levels to prevent self-destruction. If oxidative stress is too high or prolonged it can lead to death of the cancer cell.
The effects of SM-88 on ROS levels was assessed in four cell lines: two pancreatic cancer cell lines (Pan02 and PANC1) and two breast cancer cell lines (4T1 and MCF-7). In this study, following 24 hours of exposure SM-88 achieved dose dependent increases in ROS production across three of the four cell lines (Pan02, 4T1 and MCF-7) and an overall increase in the fourth (PANC1).1
Modifying Autophagy:
Autophagy is cellular catabolic degradation that often occurs in response to starvation or stress whereby cellular proteins, organelles and cytoplasm are engulfed, digested and recycled to sustain cellular metabolism. This process is utilized by cancer cells as a survival mechanism in periods when nutritional sources are low. However, cancer cells also leverage autophagy to reduce the expression of proteins that allow the body’s immune system to recognize them, such as the major histocompatibility complex 1- MHC1 in pancreatic cancer. This observation is supported by preclinical research at NYU Langone’s international center of excellence in translational and clinical research for gastrointestinal cancers as well as Yamamoto, Keisuke et al1. Therefore, disruptions of autophagy could have an impact on both viability and immune recognition of cancer cells.
In the present study, SM-88 altered autophagy in two pancreatic cancer cell lines (Pan02 and PANC1) and one ovarian cancer cell line (HeLa). SM-88 induced disruptions in autophagy were marked by elevations in LC3B and p62. Additional studies are ongoing to explore these effects and other important catabolic processes, such as mitophagy, a selective degradation of the mitochondria by autophagy.
In addition, in the PAN02 animal model, exposure to SM-88 appeared to impact tumor associated macrophages (TAMs), reducing the population of immunosuppressive M2 macrophages while preserving the more cancer directed M1 population. In addition, SM-88 treatment exhibited a dose dependent reduction in regulatory T lymphocytes, another cell type reported to create an immunosuppressive tumor environment.
Overall, these initial data suggest that SM-88 has direct effects on killing cancer cells by increasing oxidative stress and altering important processes like autophagy. In addition, SM-88 appears to cause immune modulation, creating a more toxic environment and inducing cancer cell death.
A primary goal of these preclinical studies is to help guide the company’s future clinical development of SM-88 and other novel CMBTs. These results and future experiments may help inform patient selection and identify complementary combination strategies with existing treatment options.
Inducing Immunomodulation:
Innovative therapeutics that leverage the immune system to fight cancer have demonstrated to be effective. Immuno-oncology continues to play a key role in the future treatment of cancer. Small molecule therapies that can either reduce immune suppression in the tumor microenvironment or enhance activation of cytotoxic lymphocyte responses to the tumor are actively being pursued. Unique treatment strategies with oral small molecules might be used as monotherapies or combined with other cancer therapies to increase and broaden their efficacy.
In this preclinical program, the potential effects of SM-88, as an oral small molecule, on the tumor microenvironment were evaluated. Flow cytometry was used to characterize the immune populations present in five randomly selected pancreatic cancer tumors (Pan02) collected from each group at the end of the study. Exposure to SM-88 appears to decrease intra-tumoral CD4+ T-cell populations, while preserving CD8+ populations, leading to a statistically significant (p= 0.015) decrease in the CD4+/CD8+ ratio in mice treated with the highest dose of SM-88 alone versus control. Based on these outcomes, exposure to SM-88 may decrease intra-tumoral regulatory T-cells (Tregs), a unique subset of helper T-cells, which play a critical role in reducing immunosuppressive signaling within the cancer cell. Small increases in intracellular B cell populations were also observed following treatment with oral SM-88.
Details of this preclinical study were presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Virtual Meeting from June 22 to June 24, 2020. The poster is available on our website (www.tymeinc.com/data-publications).
Details for the SM-88 poster presentation are as follows:
Title: In Vitro and In Vivo Anticancer effects of D/L-alpha-metyrosine (SM-88), a Novel Metabolism-Based Therapy
Authors: Alexander G. Vandell1, Jonathan Eckard1, Steve Hoffman1, Giuseppe Del Priore1, Martin Fernandez-Zapico2
Institutions: (1) Tyme Inc., New York, NY, (2) Mayo Clinic, Rochester, MN.
Virtual Session Date: June 22-24, 2020
Virtual Session Location: AACR (Free AACR Whitepaper) e-poster website
Abstract Number: 20-A-7314
About SM-88
SM-88 is an oral investigational modified proprietary tyrosine derivative that is believed to interrupt the metabolic processes of cancer cells by breaking down the cells’ key defenses and leading to cell death through oxidative stress and exposure to the body’s natural immune system. Clinical trial data have shown that SM-88 has demonstrated encouraging tumor responses across 15 different cancers, including pancreatic, lung, breast, prostate and sarcoma cancers with minimal serious grade 3 or higher adverse events. SM-88 is an investigational therapy that is not approved for any indication in any disease.
About TYME-88-Panc Pivotal Trial
The TYME-88-Panc pivotal trial applies the latest advances in the field of cancer metabolism by evaluating the efficacy and safety of an oral investigational compound that targets the metabolic mechanisms of the disease at its source. A prospective, open label pivotal trial in metastatic pancreatic cancer for patients who have failed two lines of any prior systemic therapy. The trial is designed to evaluate the safety and efficacy of SM-88 used with MPS (methoxsalen, phenytoin and sirolimus) in advanced pancreatic cancer and will measure multiple endpoints, including overall survival, progression free survival, relevant biomarkers, quality of life, safety, and overall response rate. Learn More.