Apoptosis Approach

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By Patricia Nicholson

Cancer research did not lead Gordon Shore, PhD, founder and chief scientific officer of Gemin X Biotechnologies Inc. (Montreal, QC), to apoptosis. Rather, studying apoptosis — programmed cell death — led Shore into cancer research.

“I was very much just a curiosity-driven basic researcher,” Shore says. “But by the early ’90s I became aware that what I was doing on a basic research side had many more implications and much more relationship to cancer in a practical consequence than I had thought when I initiated the program.”

Shore co-founded Gemin X with Philip Branton, PhD based on research they were pursuing at McGill University (Montreal, QC). Branton has since become scientific director of the Canadian Institutes of Health Research’s Institute of Cancer Research (Montreal, QC).

Vital Principle
“Phil and I were doing research in the mid-’90s — along with many other people in the world — on the relationship between cancer and apoptosis,” Shore says. “And in the mid-’90s a very important principle was emerging, and that’s the idea that cancer cells manifest signal transduction pathways that actually attempt to stimulate the cells to self-destruct by this process of apoptosis. And it was becoming very clear that cancer cells, in order to survive, had to undergo some changes that really put the apoptosis machinery out of business. Two pathways that achieve that in many cancers are defects in the p53 pathway and up-regulation of a suppressor of apoptosis called Bcl-2.

“Phil and I were working exactly in that area, and the scientific community in cancer was coming to an understanding that this question of dis-regulated apoptosis pathways in cancer was really critical, not only to the development of cancer, but also to the resistance of cancers to many current therapies — chemotherapies — because many chemotherapies actually operate by inducing apoptosis. So if the apoptosis machinery is turned off, then clearly cancers would be resistant to so many of the therapies that are currently used in the clinic.”

Shore says he and Branton saw an opportunity that they believed had the potential to translate into cancer therapeutics.

“We decided it was time to really explore that aspect of science. So we set about thinking of ways in which we could screen and identify small molecule drugs that would manipulate the apoptosis machinery, and thought about ways in which we could translate that effectively,” Shore says. “It seemed to us, given the funding situation, that the best way to pursue that was actually through commercialization, by founding a company and raising venture capital money in order to execute our plan.”

So Gemin X was founded in 1998 to discover drugs that therapeutically intervene and modulate the defects in apoptosis. The fruits of that plan are about to move into the clinic, with the company’s most advanced product — GX015-070, a Bcl-2 pan-inhibitor — slated to begin a Phase I clinical trial early this year. GX015-070 selectively induces apoptosis in cancer cells by simultaneously inhibiting multiple members of the Bcl-2 family of apoptosis suppressors.

“We’re doing an open Phase I,” Shore says of the upcoming clinical trial, which will take place at Georgetown University in Washington, D.C. “We’re following that up with a Phase I/II in chronic lymphocytic leukemia (CLL), and a Phase I in solid tumours. And after that, Phase II in solid tumours and Phase II in CLL.”

Gemin X intends to file an Investigational New Drug (IND) application for GX015-070 in the first quarter of 2004.

“It’s an extremely exciting time. A very exciting time for our investors as well. Our investors have invested many millions of dollars on the premise that we’re going to be successful in this program,” Shore says. He adds that while preclinical models can’t always predict human response, the company’s thorough research on the compound gives him confidence. “There are going to always be surprises in man, but I think that we did our homework early on, and part of the fruits of that homework is the compound that we’re going forward with.”

The company’s second product in development is GX1403, part of Gemin X’s p53-independent chemotherapeutics program that focuses on a novel chemical class of selective apoptosis modulators with activity in p53-defective cancers. Mutations in the tumour-suppressor gene p53 are implicated in many cancers. Shore explains that the protein pathway controlled by p53 is extraordinarily complex, so defects in p53 have been very difficult to tackle therapeutically. The approach Gemin X has taken is to identify apoptosis inducers that function independently of p53. Shore says the company hopes to file an IND for GX1403 in 2005.

“It has really been the goal of Gemin X to develop sustainability and pipeline so that we really can hopefully one day convert this company into something that is really quite serious on the Canadian scene,” Shore says.

Crucial Roles
Building a strong team to manage Gemin X has been crucial to the evolution of the company’s products from the discovery stage into clinical opportunities, Shore says. One key development was recruiting Dan Giampuzzi as CEO.

“Dan joined early in the life of the company and brought with him a lot of expertise. He was a former president of Searle Canada, and had experience in many, many aspects of running a company. So we were very strong not only on the research-discovery side, but we were also very strong on the business side,” Shore says. “We’re really quite proud of what Gemin X is able now to achieve, because we have very, very high-quality individuals working at the company.”

Recruiting qualified people is often a big challenge for biotech startups. Shore says there were a couple of key features that made Gemin X a winning prospect.

“Our attention to detail in terms of target validation, and as well, being in areas — apoptosis, Bcl-2, p53 — that are universally recognized as very, very important areas in cancer therapy development,” Shore says. “I think it made it a lot easier to attract people because people are knowledgeable about the importance of these areas.”

The company’s research focus was also an advantage in terms of securing funding, Shore says.

“We weren’t faced with a problem of trying to convince a very skeptical community that our particular technology is worthwhile,” he says.

Exciting Journey
In addition to his role at Gemin X, Shore is still a professor in McGill’s biochemistry department.

“I work very, very long days,” he laughs, when asked how he budgets his time. “And I’ve been very fortunate in being able to be very, very focused both at McGill and at Gemin X.”

But Shore says launching Gemin X has exposed him to new areas of science.

“All my previous exposure has been basic research — pure curiosity-driven research. So having the opportunity to translate basic research into, first of all, discovery of small molecules, then the development of small molecules through preclinical development and now through clinical development, has just been an absolutely exciting and rewarding exercise,” he says.

“Being part of an enterprise and working with a really dynamic group of people at Gemin X, who bring a lot of expertise to the table in various aspects of drug development, has really been the most exciting aspect of the journey,” Shore says. “The second part is being exposed to the business of biotechnology and drug development. That’s really what is driving — and provides the financing — in order to really accomplish something that is hopefully going to be worthwhile. In other words, have an impact on the burden of cancer in man. That has also been a very important part of what we do. I’ve been lucky enough to be exposed over the last five or six years to many new aspects that I otherwise wouldn’t have been, and it’s been a very, very exciting journey.”

The process of commercializing research has been a richly rewarding one for Shore, who says sound science and appropriate expertise are the cornerstones of the process.

“First of all, very clear proof of concept on the research side that what you’re going to pursue in terms of discovery and development is on a very sound footing — so, focusing on validated targets,” he says. “Secondly, the need to align yourself and develop and be part of a team that has the expertise to successfully make that translation. So we’re talking about a team that has experience on the research and development side as well as the business side. It sounds trivial to talk about the team, but it really is make or break — I think — in this whole process.”

Shore says he views his own role as primarily scientific, but as the founder of a biotech startup, he is very much aware of how that role fits within the framework of Gemin X.

“I see myself as a scientist who wants to have an impact on the burden of cancer in man,” he says. “I think part of the entrepreneurial spirit is being able to recognize what is important and what it takes, and to play your part and to align yourself with the right level of expertise among your colleagues. And then as a collective — everybody doing their part — you can do something that is commercially exciting and is scientifically exciting.”