S4.E4. 解鎖癌症，從癡人說夢到全面網羅

 

每年都有數百萬人被診斷出罹患癌症，而全世界的研究人員也持續努力，希望找到戰勝癌症的方法，百靈佳殷格翰也在這行列中全力以赴。我們的造浪者們更是主張積極追求突破點。

 

 

百靈佳殷格翰奧地利研究中心的負責人Darryl McConnell 回想起，當七年前他提出要挑戰KARS 基因家族時，受到的回饋都很一致：別這麼做！別碰這件事！絕對會失敗！畢竟KARS 基因家族，幾乎與各種類型的胰臟癌（pancreatic cancer）以及多種大腸癌、肺癌都有所關聯。

 

挑戰癌症驅動基因=癡人說夢？

自1980年初期，研究人員就已經注意到KARS基因在癌症中的重要性。可惜的是，到現在都還沒有人可以擊敗這項驅動基因。McConnell 試圖推動新的嘗試，卻遭眾人拒絕。「他們像看著瘋子一樣看著我」，這名澳洲人笑著回憶：「但我已經決定要做這件事。我跟他們說：我們正在這麼做，我們要讓KRAS『有藥可醫』。」

McConnell 拿起一隻黑筆，開始繪製圖型的軸；「我們可以將KRAS 想像成一個調節音量的旋鈕，音量的兩個極端分別為左右的兩個點，」然後他拿起一隻紅筆，畫了一條向上的曲線；「當癌症開始發生時代表音量突然開始急劇的變大，當細胞生長太快的時候，腫瘤就出現了。」現在，卻出現了轉機。McConnell 與他的團隊發現，如果SOS1 抑制KRAS 蛋白的突變，就有可能阻止細胞分裂（請參考右圖）。簡單來說，若能介入蛋白結構的相互作用，在另一層意義上就是讓細胞的體積變小；McConnell 又畫了一條向下的直線，臉上出現笑容。

 

 

數百萬人急迫的醫療新希望

如果這種方法在人體臨床實驗中成功，百靈佳殷格翰將能幫助數百萬人。根據德國柏林科赫研究所（Robert Koch Institute）的癌症登記中心（Center for Cancer Registry Data）所提供的數據，光是在德國，每年就有約50萬人被診斷為患有癌症；全球的患者數量則為數千萬人。因為RAS 基因突變而引發的癌症，約佔所有癌症的15%。治療方法通常為手術、放射治療、化學治療，但所有的療法副作用都只是令患者更痛苦。像McConnell 這樣具有遠見的研究人員，在百靈佳殷格翰所進行的開創性研究，更是影響醫界的關鍵。整間公司約有500名人員一起投入於開創新療法，為癌症患者帶來新希望，期望能一勞永逸治癒癌症，永除後患。

 

 

追求從根本改善患者生活的方法 

百靈佳殷格翰的研究人員以兩種方法實踐這個目標：其一，他們直接攻擊癌細胞最脆弱的一環，如：McConnel 和世界癌症研究中心（Global Cancer Research）負責人Norbert Kraut 博士，以及維也納的癌症研究團隊；另一種方法，是以免疫腫瘤學的角度切入，不依賴攻擊癌細胞的藥物，而是利用藥物，引導人體自身的免疫系統，進而能發現並破壞突變的細胞。百靈佳殷格翰三年前就開始鑽研全球癌症免疫學及免疫調節功能（Cancer Immunology and Immune Modulation function），於美國、奧地利、瑞士、德國等地成立研究部。極少有公司能做到像百靈佳殷格翰這樣，將癌細胞導向療法（cell-directed therapies）和免疫療法（immunotherapies）進行結合，雙管齊下，進而從根本上改善患者的生活。目前約有50個腫瘤治療管道（oncology pipeline）相關計畫，佔百靈佳殷格翰新開發計畫的三分之一。其中又以由McConnel 領軍的維也納團隊所進行的KRAS 抑制劑最為亮眼，最具成功的希望。

 

面對多年來的失敗和質疑，持續保持耐性

McConnell 耗費了許多年的時間才找到第一個合適的KRAS 抑制劑。他在2002年以化學家的角色，加入百靈佳殷格翰的癌症研究團隊；之後十年他都在研究細胞週期抑制劑（cell cycle inhibitor），希望能減緩癌細胞分裂的速度。他回憶說：「我們的確找到許多能抑止細胞的分子，遺憾的是，它們並不適用於患者身上。」即便面對各種質疑，我們還是得追求新的想法與突破。「聽到大家議論著我，認為這只是癡人說夢，真的很難受；但是，把『不可能的任務」化為可能，展現在別人面前，是令人非常振奮的事！」McConnell 秉持這種精神「不顧他人反對」的毅力征服KARS 突變腫瘤；至2012年，KARS 突變腫瘤仍被視為「無藥可醫」。McConnell 說：「我從來沒有預設要花多長時間完成計畫，那只是打擊士氣罷了。」

 

把『不可能的任務」化為可能，展現在別人面前，是令人非常振奮的事。 —DR. DARRYL MCCONNELL

 

 

因為決心改變而產生的新機會

McConnell 博士不氣餒，繼續尋找合作對象。來自納什維爾（Nashville）范德比大學（Vanderbilt University）的美國籍研究員Stephen Fesik 博士的資歷，完美的符合各項條件。Fesik 自2009年起開始研究KRAS，並開發了一項技術：片段篩選藥物發現（fragment-based drug discovery），可以在最困難的目標中找到適用藥物。Fesik 在Abbott Laboratories 製藥公司（現為Abbvie 艾伯維）推廣此種方法，於2000年至2009年擔任該企業癌症研究負責人。他被視為該領域的造浪者；Fesik 與Abbott的研究團隊開發了一種用以治療白血病的藥物。

Fesik 於2013年第一次接到McConnel 的電話時，並沒有太感驚訝；畢竟他時常接到許多製藥公司的定期諮詢。Fesik 直接飛到維也納，與百靈佳殷格翰的研究人員進行了為期兩天的腦力激盪。當回想那段經歷，他說：「他們確實想改變某些東西，我能很清楚的感受到他們的決心。」更讓他印象深刻的是，百靈佳殷格翰很認真的想要將「改變」化為行動；其他的公司邀請Fesik，通常都是為了讓Fesik 同意他們的做法，但在維也納發生了不同的事情，「百靈佳殷格翰的人想『聽我的』建議，並且正在採納並實施我的建議。」

 

成功獲得解鎖致癌蛋白質的鑰匙

SOS 是觸動KRAS 並保持「自動增益」（keeping the volume up）的關鍵。「若KRAS 是癌症的心臟，SOS 就是脈搏」，McConnell 說：「沒有SOS 就無法消滅KRAS。」藉由結合SOS1 抑制劑與RAS 訊息傳遞路徑中的其他關鍵蛋白質抑制劑，可以降低KRAS 的音量，維持在低數值的狀態。

最初的諮詢，發展為百靈佳殷格翰和范德比大學之間的正式合作；如今已邁入第七年。Fesik 和McConnell 依然在努力，目標為能徹底抑止KRAS。他們將能符合KRAS 蛋白表面的化合物視為「鑰匙」，試圖解開KRAS 這把鎖。藉由具備高度靈敏性的生物性測量方法，他們能精準的檢查幾乎每一個與能與蛋白質表面結合的分子。X 射線晶體學（X-ray crystallography）讓他們能精密的觀察KRAS 蛋白與化合物至原子等級（atomic level）。百靈佳殷格翰與Fesik 博士合作，不僅發現了KRAS 和其他致癌蛋白質的「鑰匙」，也因此發現許多解鎖的方法。

這兩位造浪者都認同，他們若是單打獨鬥，絕對無法達到現在的成就。McConnell 知道自己需要創新突破的思維，Fesik 則是需要百靈佳殷格翰的人手與團隊。他們攜手努力，將KRAS 抑制劑與其他藥物一起使用，以實現真正有效的治療方案。2019年9月百靈佳殷格翰與印度製藥公司Lupin 建立合作關係，Lupin 開發了MEK 抑制劑。

我能很清楚的感受到他們的決心，他們確實想改變某些東西。 —DR.STEPHEN FESIK

 

 

永遠保持希望 超前部署腫瘤免疫療法

百靈佳殷格翰與科學界以及工業領域合作夥伴，發展出一系列令人歎為觀止的多元項目（時間表如後）。關鍵的第一步，起始於2019年7月，百靈佳殷格翰收購了瑞士生技公司AMAL Therapeutics，因此強化了百靈佳殷格翰所研究的第二個重點領域：免疫腫瘤學（immuno-oncology）。

Madiha Derouazi 博士是AMAL 公司的領導者；她於2012年創辦AMAL 公司，百靈佳殷格翰風險基金就是首批的種子投資人之一。她和McConnell 以及Fesik 一樣，充滿雄心壯志：Derouazi 希望可以開發癌症疫苗；與防止感染的預防性疫苗不同，治療性疫苗可以對抗已經出現的疾病。

如同Fesik 與McConnell 的經歷，Derouazi 博士也不得不去克服接踵而來的阻力。當被問及，她的同事是否反對她的研究方向時，她笑著說：「每一個人都投反對票。」但事實證明，造浪者從不輕言放棄。AMAL 的創辦人兼執行長堅持發展她的願景；她正在研發一種癌症治療性疫苗，該疫苗含有抗體原（antigen）（蛋白質的一部分），這些抗原同樣存在於腫瘤中。這些疫苗將作驅動因子，當殺手T細胞（killer T cells）開始攻擊腫瘤時啟動免疫系統。

她與15位研究人員於日內瓦大學（University of Geneva）醫學院校區中的實驗室工作，朝著目標努力。AMAL 團隊結合多種物質成分，希望能開發有效的疫苗。研究人員運用AMAL 的KISIMA 技術平台完成整個過程。Derouazi 的辦公室裡掛著各種來自世界各地的專利證書。在KISIMA 技術平台的輔佐下，Derouazi 完成蛋白質疫苗ATP128 的開發；目前正在進行特定類型的結腸癌治療的臨床測試階段。她說，如果沒有百靈佳殷格翰的協助，不可能會有現在的成就。

「百靈佳殷格翰從一開始就以風險基金的身份給我們支持，除此之外，還提供了專家諮詢；」Derouazi 強調，「重點是，百靈佳殷格翰相信我的想法與提議，這是研究可以成功發展的原因。這也是讓我最深刻的記憶。」過去三年，AMAL 與百靈佳殷格翰的子公司Vira Therapeutics 合作；Vira Therapeutics 是位於奧地利的生物製藥公司，專供以病毒攻擊並破壞癌細胞的治療方式。

癌症，是非常狡猾又聰明的敵人。腫瘤細胞不斷的變異和變化，令自己藏匿於免疫系統中。他們的繁殖速度之快，導致人體的防禦能力無法因應。百靈佳殷格翰不只規劃並且超前部署多種免疫療法，也同時融合其他腫瘤細胞特定治療法。Amal 在阿拉伯文為希望的意思， Amal 公司也是希望的關鍵。

 

合作而更強大

創新的解決方案，時常由合作關係中誕生；百靈佳殷格翰也有一樣的體會。2019年，百靈佳殷格翰為了打贏對抗癌症的戰爭，拓展了腫瘤治療組合方案。時間軸如下：

 

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 (see info graphic on page 17). Intervening in this protein-protein interaction would – metaphorically – turn the volume in the cells back down; McConnell sketches a downward stroke and smiles.

 

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.

 

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.”

 

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.”

 

CLINICAL STUDY LAUNCHED

SOS is responsible for turning KRAS on and keeping the volume up. “If KRAS is the beating heart of cancer, then SOS is its pacemaker,” says McConnell. “KRAS can’t beat without SOS.” By combining SOS1 inhibitors with inhibitors of other key proteins in the RAS signaling pathway, it could be possible to turn down the KRAS volume – and keep it down.

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.

 

A CANCER VACCINE

Boehringer Ingelheim relies on collaboration with partners in science and industry around an incredibly diverse range of projects (see timeline on page 19). 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.

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 compo- nents 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.