A two-pronged attack on cancer

Each year, millions of people are diagnosed with cancer. Researchers all over the world are searching for ways to win the fight against this disease. Boehringer Ingelheim is searching as well. The company’s pioneers have defied the skeptics – and are now hoping for a breakthrough.

The advice was unanimous: Don’t do it! Don’t touch it! It’s guaranteed to fail! Dr. Darryl McConnell, Boehringer Ingelheim’s Research Site Head in Austria, sits in his office in Vienna recalling the reactions seven years ago, when he presented the idea to take on KRAS. This protein from the RAS family is responsible for nearly every type of pancreatic cancer and many forms of colon and lung cancer.

Researchers have been aware of the significance of KRAS for cancer since the early 1980s. To date, however, none have managed to beat this driver of cancer. McConnell wanted to hazard a new attempt – but people shook their heads. “They looked at me like I was crazy,” remembers the Australian with a laugh. “But I wanted to. I said: We’re doing it, we’re going to drug KRAS.” McConnell picks up a black pen and starts sketching the axes of a graph. “You can think of KRAS like a volume knob. The volume might normally be set at around ‘two,’ for example,” he says, and marks a point. Then he picks up a red pen and draws a curve that shoots upward. “When cancer develops, the volume suddenly increases sharply. Then the cells grow far too quickly – tumors emerge.” Now, however, there is hope. McConnell and his team discovered that if the activation of the KRAS protein was obstructed by the protein SOS1, cell division could be impeded. Intervening in this protein-protein interaction would – metaphorically – turn the volume in the cells back down; McConnell sketches a downward stroke and smiles.

Showing what’s possible is much more exciting than talking about what’s not.

DR. DARRYL MCCONNELL

ACUTE MEDICAL NEED

If this approach succeeds in clinical trials with humans, Boehringer Ingelheim could help millions of people. According to the Center for Cancer Registry Data at the Robert Koch Institute, Berlin, around a half-million people are diagnosed with cancer each year in Germany alone; the global figure is in the two-digit million range. RAS-driven varieties of cancer account for roughly 15 percent of all cancers. The tumors are typically treated with operations, radiation or chemotherapy, all of which have side effects that cause patients even more distress. This makes the work of visionaries like McConnell who do pioneering research at Boehringer Ingelheim all the more crucial.

Roughly 500 researchers throughout the company are developing innovative therapies to give cancer patients new hope – and to win the fight against cancer once and for all.

The family-owned company has shown a great deal of perseverance when it comes to developing new and innovative therapies for cancer. Its researchers pursue this through two approaches. In one, they attack cancer cells directly at their Achilles’ heel, like McConnell and Dr. Norbert Kraut (Head of Global Cancer Research) and their teams of cancer researchers in Vienna. The second approach comes from immuno-oncology: Instead of relying on medicines that attack the cancer cells, medicines are used that direct the body’s own immune system to find and destroy mutated cells. To this end, Boehringer Ingelheim established the global Cancer Immunology and Immune Modulation function three years ago, which is spread across locations in the US (Ridgefield, CT), Austria ( Vienna, Innsbruck), Switzerland (Geneva) and Germany (Biberach). It is unique that a company pursues a dual approach of combining cancer cell-directed therapies and immunotherapies enabling combinations that stand to fundamentally improve the lives of patients. There are currently more than 50 projects in the oncology pipeline, accounting for roughly one-third of Boehringer Ingelheim’s new developments. Of these, the findings of McConnell and the team in Vienna, who are working with an entire armada of KRAS inhibitors, are especially promising.

KRAS is responsible for nearly every type of pancreatic cancer and many forms of lung cancer.

PATIENCE IS A MUST

Years passed before McConnell found the first suitable KRAS inhibitor. A chemist, he first joined the cancer research team at Boehringer Ingelheim in 2002. For the first ten years, he researched cell cycle inhibitors in the hope of being able to slow the division of cancer cells. “We did manage to find a number of molecules that inhibit the cell cycle,” he recalls. “Unfortunately, they didn’t work in patients.” After that, new ideas were needed – even in the face of skepticism. “I find it hard to listen when people say something is impossible. Showing what’s possible is much more exciting than talking about what’s not,” says McConnell. It was in this spirit – against all advice – that he took on KRAS-mutated tumors, which were still considered untreatable in 2012. “When I’m facing a major goal, I never think about how long it might take to achieve it,” McConnell says. “That would be demoralizing.”

DR. STEPHEN FESIK

A pioneer in KRAS research, Fesik has been working with Boehringer Ingelheim for seven years now to shut off KRAS entirely.

NEW OPPORTUNITIES THROUGH PARTNERSHIPS

Instead, McConnell looked for someone to team up with. US researcher Dr. Stephen Fesik from Vanderbilt University in Nashville fit the profile. Fesik had been researching KRAS there since 2009 and had developed a new technology: fragment-based drug discovery, an innovative approach that can find drugs for the toughest targets. Fesik had advanced this approach at the pharmaceutical company Abbott Laboratories (now AbbVie), where he had been working from 2000 to 2009 as the head of cancer research. He is considered a pioneer in his field; Fesik and colleagues at Abbott developed a medication, which is used to treat leukemia.

When McConnell called Fesik in 2013, he was unsurprised, because many pharmaceutical companies consulted him regularly. Fesik flew to Vienna for two days – and was met with a storm of questions from Boehringer Ingelheim’s researchers. “It was very clear to me that they truly wanted to change something.” What impressed him even more, was the fact that Boehringer Ingelheim was truly interested in a serious exchange. Other companies had invited Fesik to agree with their ways of doing things. In Vienna, the situation was different. “They wanted my opinion, and they have implemented my advice.”

The initial consulting service turned into a formal cooperation between Boehringer Ingelheim and Vanderbilt University which is now entering its seventh year. Today, Fesik and McConnell are working together to shut off KRAS entirely. They pursue this by searching for structures to serve as “keys” that fit exactly into the “locks” on the surface of the KRAS protein. Thanks to highly sensitive biophysical measurement methods, they can precisely examine nearly every molecule that binds to the protein’s surface. Using X-ray crystallography, they can view the “keys” and “locks” all the way down to the atomic level. Thanks to this cooperation with Fesik, Boehringer Ingelheim has discovered not just one but a number of such “keys” to KRAS and other cancer-causing proteins.

The two pioneers agree that they would never have made it so far on their own. While McConnell knew that he needed to blaze entirely new trails, Fesik needed Boehringer Ingelheim’s manpower. Working together, the two of them realized that they needed to combine the KRAS inhibitors with other medications to achieve real options for treatment. In September 2019, Boehringer Ingelheim entered into a partnership with the Indian pharmaceutical company Lupin, which had developed what is known as a MEK inhibitor.

DR. MADIHA DEROUAZI

The founder of AMAL combines components to make an effective vaccine.

A CANCER VACCINE

Boehringer Ingelheim relies on collaboration with partners in science and industry around an incredibly diverse range of projects. One major step was the acquisition of the Swiss biotech firm AMAL Therapeutics in July 2019, which strengthened the second key strand of cancer research at Boehringer Ingelheim: immuno-oncology.

At the head of AMAL stands Dr. Madiha Derouazi. When she founded the company in 2012, the Boehringer Ingelheim Venture Fund was one of its first seed investors. Her vision is no less ambitious than that of McConnell and Fesik: Derouazi wants to develop a cancer vaccine. In contrast to prophylactic vaccines, which aim to prevent the outbreak of an infection, a therapeutic vaccine such as this would serve to combat illnesses which have already emerged.

Like McConnell and Fesik, Derouazi has also had to overcome resistance. She responds to the question of whether her colleagues advised against her research with a laugh. “Everyone did.” But it turns out pioneers don’t give up so easily. The founder and CEO of AMAL has stayed true to her vision; she is working to develop a cancer vaccine that will carry antigens, i.e. parts of proteins, which are also found in tumors. Such a vaccine will serve to activate the immune system, particularly its “killer T cells,” which will then attack and destroy the tumor.

Boehringer Ingelheim believed in my idea and supported me – which is what got the research going. That made a lasting impression on me.

DR. MADIHA DEROUAZI

She works toward this goal with a team of 15 researchers in a laboratory at the University of Geneva’s medical campus. The AMAL team combines various components to develop an effective vaccine. The researchers carry out this process using AMAL’s KISIMA technology platform. Patent certificates from all over the world hang alongside the file cabinet in Derouazi’s office. With the help of KISIMA, Derouazi developed the protein vaccine ATP128, which she is now testing in a clinical trial on the treatment of a specific type of colon cancer. This would be impossible without Boehringer Ingelheim, she says.

“From the very beginning, the Boehringer Ingelheim Venture Fund supported me not only with financial assistance, but also with specialist support,” Derouazi emphasizes. “Even then, Boehringer Ingelheim believed in my idea – which is what got the research going. That made a lasting impression on me.” For the last three years, AMAL has also cooperated with Boehringer Ingelheim subsidiary Vira Therapeutics, a biopharmaceutical company from Innsbruck, Austria, that specializes in researching therapies with viruses that destroy cancer cells.

Cancer, however, is an extremely clever foe. Tumor cells conceal themselves from the immune system by constantly mutating and changing. They also multiply so quickly that the body’s defenses can scarcely keep up. It is for this reason that Boehringer Ingelheim plans not only to deploy multiple immunotherapies in parallel, but to also combine them with additional tumor cell-specific therapies. And AMAL will play a crucial role in this as well, guided by the meaning of the company’s name “Amal”, the Arabic word for hope.