TheraPten Biosciences Inc., a Canadian biotechnology company, has entered into an exclusive licensing agreement with Columbia University on two globally issued patent families covering PTEN-L, a naturally-occurring tumor suppressor protein.
PTEN-L is a translational variant of PTEN, a major regulator of cell fate in humans and animals. Both PTEN and PTEN-L are potent tumor suppressor proteins that are functionally inactivated in many human cancers. PTEN was discovered in 1997 by a team led by former Columbia University Professor Ramon Parsons. Clinical trial data meta-analyses of thousands of brain, breast, prostate, and lung cancer patients reveal that higher levels of PTEN are correlated with improved survival rates. Conversely, PTEN loss is a powerful prognostic factor for low survival in these patients.
The naturally-occurring variant form of PTEN, originally called PTEN-Long and now referred to as PTEN-L, was also discovered by Parsons and his team at Columbia University. Unlike PTEN and all other known tumor suppressors, which are all unable to cross the cell membrane and thus have no therapeutic value, only PTEN-L naturally penetrates the membrane of many cancer cells. As such, when introduced into cancer cells PTEN-L displays potent anti-cancer action in animal models of cancer and induces tumor cell death.
Through its licensing agreement with Columbia, TheraPten seeks to optimize PTEN-L as a therapeutic agent that restores this critical tumor suppressor protein to malignant cells. In addition, the company aims to develop novel therapeutics using PTEN-L’s unique cell-penetration domain (LUD) as a technology platform for intracellular delivery of therapeutic proteins, such as other tumor suppressors or antibodies for intracellular targets. Previous work under the licensing agreement has demonstrated effective cellular entry and tumor regression by a LUD-p53 fusion protein allowing the most mutated human tumor suppressor, p53, to be introduced as a potential therapeutic to cancer patients.
“We are pleased to announce the exclusive licensing agreement with Columbia University to develop PTEN-L as a unique, promising cancer therapeutic, said Nassos Alevizopoulos, PhD, MBA, CEO and Chairman of TheraPten. “The role of PTEN loss in all major tumors has been well documented across thousands of studies, and the discovery of PTEN-L, which is naturally-occurring and membrane permeable, has enabled a novel approach to replacing this crucial cell growth regulator protein across a wide range of malignancies. Our goal is to manage human cancer with a straightforward injection of our body’s natural anti-cancer defense protein.”
A Conversation with Nassos Alevizopoulos, CEO and Chairman, TheraPten (NA), and Ramon Parsons, Chief Scientific Advisor, TheraPten and Prof. at the Icahn School of Medicine at Mount Sinai, New York (RP).
Were you looking for a tumor suppression gene when PTEN was identified?
RP: Yes, we knew there was likely to be a tumor suppressor gene located on chromosome 10 from a variety of different studies in glioblastoma, prostate cancer and an inherited cancer syndrome. We discovered PTEN by mapping chromosome 10 deletions in breast, prostate, and glioblastoma. We sequenced DNA from the smallest deletion, which led to the discovery of a gene we named PTEN. We immediately sequenced the gene in cancer cells, and saw that there were many coding mutations. We knew early on that a variation of PTEN existed, as we always saw a larger form of PTEN by western blot that we could not explain. Eventually, we identified this form as PTEN-L.
How can PTEN-L be used therapeutically?
NA: The PTEN protein is missing or mutated in most cancer cells, thereby facilitating cancer progression. Along the first licensed patent, we will synthesize PTEN-L externally and inject it back into the patient, so that it can exert its natural function - replenish active PTEN tumor suppressor into the cancer cell. It’s like a reset for the cell. The second patent covers the usage of PTEN-L as a vehicle for shuttling molecules or proteins into cells, much like a Trojan horse (protein therapy). The concept is superior to gene therapy which uses viruses to deliver a gene into the faulty tissues and hope that the gene will express functional protein. In contrast, the LUD will naturally shuttle active protein into the cells directly without viruses or delivery issues. In theory, we can fuse almost any protein to PTEN-L and transport it into cells, and that leads to a lot of exciting possibilities, e.g. in rare diseases.
Describe what you’ve observed in testing PTEN-L thus far.
NA: Our preliminary testing shows that this protein exerts a very strong anti-cancer action in mice. In select cases cancer disappeared from the animals even though the therapy has not yet been optimized. We’re also encouraged by early tests showing that PTEN-L has a very high therapeutic index—it’s performing the function we expect, and with very little toxicity.
Speaking of off-target effects, are there any potential downsides to having more PTEN?
NA: That’s an interesting question, and the answer highlights the beauty of this protein. During our initial discussions with Dr. Parsons, we noticed two seminal papers written by Manuel Serrano of Madrid University and Pier Paolo Pandolfi at Harvard. Both independently overexpressed the PTEN gene in mice. I should note that the papers had been published before it became known that the gene was making PTEN and PTEN-L. In both cases, when mice were forced to make more PTEN, and presumably more PTEN-L as well, the mice became strongly cancer-resistant and had greater longevity. So elevating the PTEN proteins might increase life expectancy in both health and disease - It’s quite intriguing.
How does PTEN fit in the context of immuno-oncology?
NA: Immuno-oncology antibodies and newer therapies like CAR-T are very useful anti-cancer treatments. However, CAR-Ts require a lot of in vitro manipulations and so their manufacturing cost is high. PTEN-L’s manufacturing cost will be at par or lower than that of I-O antibodies. More importantly, cancer patients who lost PTEN appear to respond poorly or develop resistance to these antibodies. Thus, there is bright future for PTEN-L as a natural human therapeutic.
What are the next steps for TheraPten?
NA: In addition to our agreement with Columbia, we are proud to have a preclinical development partnership with the Canadian National Research Council in Montreal. Right now, we’re working with them to manufacture the protein and begin our initial efficacy & safety studies. We know that PTEN loss is associated with so many cancers, but our approach to bringing this to the clinic will build on previous work at Columbia on brain cancer, triple negative breast cancer, and renal cancer. Those areas are particularly interesting for us.
source Columbia Technology Ventures