S5. E5. 直擊致癌的關鍵基因 KRAS COALITIONS AGAINST CANCER

 

百靈佳殷格翰的研究人員正在尋找能根治癌症的驅動基因：KRAS 蛋白，並為了促成更多醫療方案的新排列組合，開發新的合作夥伴關係。

因為 KRAS 基因的重要性，讓它擁有「癌症的心臟」之稱，也因此獲得科學家們的高度重視。KRAS 不只促進癌細胞的生長，也是最容易突變的致癌基因，與各種類型的胰臟癌、多種大腸癌、肺癌都有所關聯。即便人們已經深刻了解 KRAS 的重要性，卻幾乎沒有人敢與這種蛋白質抗爭，因為目前沒有任何藥物分子能與 KRAS 基因結合，大部分的人都秉持著絕望的心態，也因此導致了 KRAS 基因相關癌症「無藥可醫」的困境。

百靈佳殷格翰全球癌症研究中心（Global Cancer Research）負責人 Norbert Kraut 博士說：「過去40年來，所有 KRAS 抑制劑的試驗都失敗了。但，如今出現了兩種充滿希望的方法：一個是直接綁定 KRAS 基因，一個是用 SOS1 抑制 KRAS 蛋白，使之喪失活性。」

每一種 KRAS 蛋白都不一樣。KRAS 基因可以突變為非常多種狀態，出現在細胞中：所有因 KRAS 突變而引發的癌症，就有 9 種不同的 KRAS 基因。KRAS G12C 為其中一種突變狀態，發生在約 15% 的非小細胞肺癌（non-small cell lung cancers）。有些製藥公司已經開始為此研發分子，並在早期臨床試驗中取得正面的成果，以阻隔的方式抑制 KRAS。百靈佳殷格翰也投入於這波研發之中，其專有的 G12C 抑制劑將於 2021 年啟動臨床試驗。 Kraut 博士表示：「雖然這不是第一個以這種模式處理的藥物，但我們相信，這是一個非常有發展性的解決方案。」百靈佳殷格翰運用被稱為片段（segment）的小分子藥物，辨識出可能的結合點。

KRAS G12C 是 KRAS 突變最常見的第三種型態。因 KRAS 突變導致癌症的案例中，有 50% 來自於 KRAS G12D 和 KRAS G12V 突變。到目前為止，尚未發現具備發展性的pockets，或可以控制該分子的鎖鑰。

BI 1701963 是百靈佳殷格翰的 pan-KRAS 抑制劑，可能有助於抑制這些類型的基因突變，藉由停止蛋白質活性防止 KRAS 基因突變。Kraut 表示：「如果沒有SOS1，KRAS 就沒辦法停止工作。」SOS1 抑制劑與其他抑制劑的組合，或許能永久抑制 KRAS 基因突變，甚至有可能抑制其它多種類型的基因突變，將不可能化為可能。Kraut 補充說明：「研發分子 BI 1701963 的目的．在於抑制導致多種癌症發作的 KRAS 基因突變。」Kraut 表示，臨床前數據已證實 pan-KRAS 抑制劑可對許多實驗中的 G12 和 G13 KRAS 基因起作用，在基因突變中阻斷腫瘤的生長。

 

KRAS基因突變導致各種類型癌症發生的機率：

 

 

 

 

 

百靈佳殷格翰正在與生命科學領域的夥伴合作，希望可以在聯合治療方案領域更快的取得進展。2019年9月，百靈佳殷格翰與印度製藥公司 Lupine Limited 結盟，擴大KRAS 癌症計畫。百靈佳殷格翰已經取得授權，將MEK（RAS 訊息傳遞（signal pathway）的其中一個關鍵蛋白質）抑制劑作為數個可能的SOS1組合之一。

2020年9月，百靈佳殷格翰開始與美國生物科技公司Mirati Therapeutics 合作，一起進行臨床試驗，測試百靈佳殷格翰的 pan-KRAS 抑制劑與 Mirati 公司的 G12C KRAS 抑制劑藥物 adagrasib（MRTX849）的組合。在最早啟動的 I 期研究中，將會確認這種組合，是否能更有效的治療因 KRAS G12C 基因突變而罹患肺癌或結腸癌的患者。

Kraut 在談到這些合作關係時，認為：「這是一個雙贏的局面。」雙方都相信抑制劑的相互作用，能使患者受益；合作為推動、改善治療方案的進度帶來非常大的助益。Kraut 又補充道：「在臨床前研究中，我們已經發現許多種因 KRAS G12C 突變而驅動的腫瘤，都能進行治療。這是一個充滿積極與希望的起點。」

百靈佳殷格翰與Mirati的合作關係建立在過去百靈佳殷格翰與德州大學安德森癌症中心（ MD Anderson Cancer Center，美國最大的癌症中心之一）的長期合作基礎上。美國的科學家們被視為全球癌症研究的造浪者，專長包含大範圍的研究，並擁有大量患者數據。他們能組織新的合作關係，並發展可能的臨床試驗。Kraut 說：「我們不隨便與其它單位合作。這些夥伴關係必需具有相互依存性，互助互益，因此能加速我們在癌症研究的發展，訂定更明確的目標。」

不久的將來，我們可能會有更多的合作夥伴。在檢視年度策略時，管理董事會宣布：百靈佳殷格翰將在研究領域—尤其是腫瘤學領域—投入更多資金。Kraut 補充：「這代表我們能在更多領域中，進行更多類型的研究，建立進一步的合作關係。這一切都能更明確的提升患者健康，帶來改變。」

 

9種關鍵KRAS基因

90%以上的癌症發生，與以下KRAS基因突變相關

 

 

 

 

 

 

 

「SOS1 抑制劑與其它抑制劑的組合，或許能永久抑制 KRAS 基因突變，甚至有可能抑制其它多種類型的基因突變，將不可能化為可能。」

百靈佳殷格翰全球癌症研究中心（Global Cancer Research）負責人

Norbert Kraut 博士

 

 

 

 

 

COALITIONS AGAINST CANCER

Researchers at Boehringer Ingelheim are seeking to eradicate one of the key drivers of cancer – the KRAS protein. New partnerships are intended to enable combination treatments that help to tackle different mutations.

Scientists have great respect for KRAS. Due to its importance, they refer to this protein from the RAS family as “the beating heart of cancer”. KRAS promotes the growth of cancer cells; it is the most frequently mutated cancer-causing gene – and it is responsible for virtually every type of pancreatic cancer as well as many forms of intestinal and lung cancer. Moreover, even though KRAS’ significance for cancer has long been understood, hardly anyone had dared to combat the protein. It was thought to be hopeless – KRAS appeared not to have any sites that medicine molecules could bind onto, and it was considered untreatable.

“For nearly 40 years, every attempt to develop inhibitors has failed,” says Prof. Dr. Norbert Kraut, Global Head of Cancer Research at Boehringer Ingelheim. “However, there are now two promising approaches: On the one hand, binding KRAS directly. And on the other, blocking its activation through SOS1.”

Not all KRAS proteins are alike. KRAS occurs in many mutant forms in the cell: Nine different KRAS mutants cause over 90 percent of all KRAS-driven cancers. One form is the driver mutation KRAS G12C, which occurs in around 15 percent of non-small cell lung cancers. Some pharmaceutical companies have already developed molecules for this that have yielded positive results in early clinical studies. They freeze KRAS in off mode. Boehringer Ingelheim is also taking part in this race. Its proprietary G12C inhibitor is set to undergo clinical testing in 2021. “We are not the first to do this, but we believe we have a very promising product,” says Kraut. This inhibitor makes use of a binding site which Boehringer Ingelheim has identified by means of small pieces of drug molecules known as “fragments”.

KRAS G12C is only the third most common form of mutated KRAS. The mutations KRAS G12D and KRAS G12V account for more than half of the total number of cancers caused by KRAS. Unlike in the case of G12C, no promising pockets or locks for substance molecules to attach themselves to have been identified for these mutations so far.

BI 1701963 – the pan-KRAS inhibitor of Boehringer Ingelheim – may be helpful in dealing with all of these mutations. It prevents KRAS from being switched on by blocking the activator protein SOS1. “KRAS cannot strike without SOS1,” Kraut notes. The combination of SOS1 inhibitors with other inhibitors might make it possible to inhibit KRAS permanently – and in virtually all of its mutations. “The molecule BI 1701963 was developed with the goal of inhibiting a wide range of oncogenic KRAS vari- ants,” Kraut remarks. Pre-clinical data has con- firmed that the pan-KRAS inhibitor blocks tumor growth in many of the G12 and G13 KRAS gene mutations tested.

 

KRAS MUTATIONS OCCUR WITH MUTATION RATES OF MORE THAN:

 

 

 

 

 

 

Boehringer Ingelheim is working with partners across the life science community in order to achieve faster progress in researching such combination treatments. In September 2019, Boehringer Ingelheim expanded its KRAS cancer program through a partnership with the Indian pharmaceutical company Lupin Limited; Boehringer Ingelheim has in-licensed an MEK inhibitor as one of several potential SOS1 combination partners. MEK is another key protein in the RAS signal pathway.

Moreover, in September 2020, Boehringer Ingelheim announced its clinical partnership with the US biotech company Mirati Therapeutics in order to test a combination of the pan-KRAS inhibitor of Boehringer Ingelheim and Mirati’s G12C KRAS inhibitor adagrasib (MRTX849). The potential of this combination as a more effective treatment option for people with lung or colon cancer with a KRAS G12C mutation will be ex- amined in an initial Phase I study.

“We consider this a win-win situation,” says Kraut in reference to the partnership. Both partners are convinced that the interaction of their inhibitors will benefit the patient – and that their cooperation provides a fast way to achieve a genuine improvement in the therapy options. “In pre-clinical studies, we have seen that many of the KRAS G12C-driven tumors treated shrink; that is a very positive starting point.”

The partnership with Mirati will build on the longterm collaboration of Boehringer Ingelheim with the MD Anderson Cancer Center at the University of Texas, one of the largest cancer clinics in the United States. American scientists are seen as world leaders in cancer research, their expertise includes a broad range of study and patient data. They could be able to conduct potential clinical studies on behalf of the new partners. “We don’t enter into partnerships at random. Our partnerships build on one another; they supplement one another, and they thus all support our goal of achieving faster and genu- ine progress in fighting cancer,” says Kraut.

More partnerships may follow in the near fu- ture: In its annual strategy review, the compa- nies board of managing directors announced that, in the medium term, Boehringer Ingelheim intends to invest even more strongly in research and, in particular, in its oncology pipeline. “That means we will be able to conduct more research on a broad front and enter into further partnerships,” Kraut comments. “And all of that with the goal of achieving a decisive improvement of patients’ health.”

 

NINE KRAS MUTANTS ARE KEY

They cause over 90 percent of all KRAS-driven cancers

 

 

 

 

 

 

 

“The combination of SOS1 inhibitors with other inhibitors might make it pos- sible to inhibit KRAS permanently,” says Prof. Dr. Norbert Kraut, Global Head of Cancer Research at Boehringer Ingelheim.