Standard treatment options had failed, and the young woman was given only a few months to live. An aggressive tumor had spread from the muscles of her back, to her pelvis, and throughout her abdominal cavity. Desperate for more time, the woman volunteered to receive an experimental drug compound called SM-88, a novel oral compound that targets the rampant spreading of tumors and tricks cancer cells into consuming a modified dysfunctional metabolite.

The effect on the woman’s disease was profound. The drug shrunk the tumors to the point that they could be safely excised. The woman lived another five years, thanks to this experimental anti-cancer agent.

Amazed, her doctors consulted cancer specialist, Dr. Giuseppe Del Priore. “I had done device and drug development for decades, and this was certainly a transformational experience,” he says.

After seeing a few more patients with similarly astonishing responses, Del Priore quit his day job at one of the largest cancer treatment organizations in the United States and joined TYME Technologies Inc., an emerging biotechnology company and the innovator of SM-88. “I just believed in the drug that much,” he says.

As chief medical officer of the New York-based company for the past four years, Del Priore has shepherded SM-88 through several trials that have collectively shown the drug’s potential to treat tumors of the breast, prostate, lung and numerous other organ systems. But the most promising clinical data come from studies of pancreatic cancer, a notoriously complex disease with few reliable therapeutic options.

In 2019, the company reported interim results from its TYME-88-PANC trial of patients with heavily pretreated pancreatic cancer: a population typically referred for palliative care. After their first treatment fails, pancreatic cancer patients are generally only expected to survive a few months due to the cancer’s very rapid growth. On SM-88, many of the study participants had their tumors shrink or stop growing, and TYME continues to follow patients’ progress a year after the study had fully enrolled.

Importantly, the patients paid “such a low price in terms of side effects,” says Allyson Ocean, a medical oncologist at Weill Cornell Medicine, in New York City, who has treated a number of patients on SM-88. Some study subjects developed mild skin discoloration or experienced brief bouts of fatigue after receiving the drug. But SM-88 “really doesn’t make them sick,” Ocean says. “To me, that’s the unique differentiating feature of this molecule compared to other therapies that have very challenging side effects.”

A patient-centric approach

With plans to make SM-88 broadly available to pancreatic cancer patients, TYME has since launched a pivotal, randomized trial evaluating SM-88 against standard-of-care chemotherapy for patients who have failed other available treatments. In parallel, the company has joined forces with the Pancreatic Cancer Action Network (PanCAN), an advocacy, research and support group with a strong national presence, to make SM-88 available to patients with advanced metastatic pancreatic cancer, through the organization’s Precision PromiseSM trial.

“It’s a compound that is being developed in multiple lines of therapy,” notes Victoria Manax, chief medical officer of PanCAN, and a member of TYME’s medical advisory board. She says the company is committed on putting patients at the center of their development plans.

The Precision Promise trial will start in late 2019 with an adaptive design, meaning that therapies deemed effective will be further evaluated, while those showing little potential will be phased out of the study. SM-88 is the first investigational agent included in the multi-drug trial, in part, says Manax, because its “mechanism of action was something that holds great interest.”

SM-88, at its core, is simply a collection of molecular building blocks — albeit one that disrupts the manufacturing of proteins inside cancer cells. The drug includes a form of tyrosine, an amino acid that most healthy cells can produce on their own, but which cancer cells must consume to fulfill their high energy demands. This tyrosine gets pulled into the cancer cell though specialized receptors on its surface, but is generally not absorbed by normal healthy cells.

This novel, modified tyrosine is a mirror image of normal tyrosine, but that chemical distinction makes all the difference. Life has not evolved to use amino acids carrying that modification, and the protein-making factories of the cell get tricked into trying — but failing — to proceed with the backwards tyrosine. “That basically gums up the cancer cell’s machinery,” says Jonathan Eckard, chief business officer of TYME.

Protein synthesis then fails. On the outside, the cancer cell is unable to secrete proteins called mucins that normally protect tumors against immune attack; while internally, the cell struggles to deal with damaging molecules called free radicals. TYME administers SM-88 together with three other drugs designed to amplify the effects of SM-88. The net result: the toxic imbalance and immune onslaught ultimately lead to cancer cell death.

Metabolic malware

The strategy pivots on a century-old idea, first proposed by the German biochemist, Otto Warburg, that cancer cells metabolize energy differently to normal cells. Whereas normal cells typically employ two modes of energy production — one when oxygen is abundant, another when oxygen is scarce — cancer cells rely on the low-oxygen route for survival.

This ‘Warburg effect’ results in elevated consumption of many biomolecules, including amino acids such as tyrosine. The increased demand for tyrosine leads to an increased reliance on exogenous supplies, and SM-88 feeds that dependence with the equivalent of metabolic malware. 

That is the leading hypothesis at least. To fully reveal the drug’s mechanism, in July 2019 TYME announced a new collaborative research partnership with pancreatic cancer surgeon, Dr. Diane Simeone, and her colleagues at New York University’s Perlmutter Cancer Center. The goal is now to examine the effects of SM-88, together with other therapies, in cell lines, mouse models and three-dimensional tissue cultures. Through these laboratory experiments, TYME hopes to identify beneficial drug combination strategies and diagnostic biomarkers that could guide future clinical development.

Part of those plans involves moving ahead with trials concurrently in multiple types of cancer. In prostate cancer, for example, early studies suggest SM-88 may provide disease control with fewer side effects than standard hormone therapy. And recently, the company initiated a trial for patients with high-risk sarcomas.

SM-88 was specifically designed to target the cancer cell and spare the patient’s healthy cells. To date, that has been proven in clinical trials.  SM-88 has demonstrated confirmed responses in patients across 15 different tumor types with only two out of approximately 180 patients having serious adverse events, possibly or probably, related to SM-88. For perspective, the most commonly used pancreatic cancer regimens have more than 50% of patients experiencing drug related serious adverse events

For now, TYME is strategically advancing SM-88 for those metastatic cancers with few other treatment options — diseases for which the novel metabolism-altering agent stands to make the biggest therapeutic impact. However, given the drug’s safety profile and early signs of efficacy across a dozen different tumor types, Del Priore anticipates SM-88 may eventually demonstrate its worth.

“This could replace or reduce the need for other toxic treatments for cancer care,” he says. “SM-88 could potentially fill a critical need for patients across a variety of diseases.”

To learn more about SM-88 and the ongoing trials, visit Tyme Technologies.