Cancer cell directed therapies
At Boehringer Ingelheim, we have made a generational commitment to transforming cancer care, with the ultimate goal of curing a range of cancers. We are investigating cancer cell directed therapies that target key cancer drivers and hallmarks to directly kill cancer cells. In parallel, within immune cell directed therapies, we are exploring new ways of directing and boosting the immune system against cancer cells. We consider that it is the smart combination of these approaches that could offer the greatest benefit for people living with cancer.
Cancer cell-directed therapies: targeting cancer at its heart
We are identifying approaches to tackle the major cancer drivers, including HER2, KRAS and p53. These proteins are mutated in more than half of all cancers, and they drive key cellular processes involved in the initiation and growth of tumors. Research topics in cancer cell directed therapies:
Block aberrant cancer cell signaling
We are highly interested in targeting the KRAS oncogene, with the aspiration of changing the lives of potentially one in seven cancer patients with tumors harboring mutated KRAS. While the first covalent inhibitors of the KRASG12C variant received FDA approval for non-small cell lung cancer (NSCLC) patients, there is still a need to address other prevalent KRAS variants. Expanding the spectrum of targetable KRAS forms has become central to our strategy. We have several clinical and preclinical programs targeting a broad spectrum of oncogenic KRAS variants. The first clinical KRASmulti inhibitor is currently being investigated in patients in Phase I.
Another key target is the tyrosine kinase receptor HER2. Mutations in the HER2 gene are seen across different cancer types, including breast, gastric and lung cancer. Every year, about 40,000 people worldwide are diagnosed with non-small cell lung cancer (NSCLC) driven by an activating HER2 mutation. Successfully addressing HER2 mutations requires active but also selective drugs. This ensures that that patients can benefit from the effects of the drug on the cancer without suffering limiting side-effects. We discovered a highly selective and potent small molecule inhibitor of HER2, which is being developed as an oral treatment for patients with specific mutations in the HER2 gene and is currently in clinical trials Phase III.
Induce tumor cell death
We are exploring the next wave of therapeutic targets leveraging the knowledge of NBE Therapeutics. During the last decade, Antibody-Drug Conjugates (ADCs) have become an important and validated treatment modality for patients with cancer. Applying Paul Ehrlich’s principle of the “magic bullet”, ADCs selectively target cancer cells using a tumor-associated antigen engaged by an antibody. This is linked to a cell death-inducing payload which gets activated upon entering the cell.
The ADCs preclinical portfolio is expanding, and teams are searching for innovative strategies to attack cancer cells. Our technology is designed to generate very homogenous and stable drug conjugates with limited systemic but powerful anti-tumor activity. The next wave of ADC programs has already begun and is successfully showing early proofs of concept in cellular systems and mouse models.
Restoration of tumor suppressive transcription
Mutation or deregulation of transcription factors can cause aberrant gene expression, including the blockade of cell death and cell differentiation transcriptional programs. Transcription factor activity is altered in the majority of cancers and therefore represents a promising although challenging class of targets. Approaches to therapeutically address transcription factor activity can include directly targeting the transcription factor itself, as well as transcriptional co-activators and co-repressors, epigenetic regulators, and chromatin modifiers
Furthermore, cell death pathways are activated in the presence of environmental stresses including exposure to mutagens such as cigarette smoke or ultraviolet light. Cancers need to deactivate these pathways. One of the key environmental sensors is the tumor suppressor protein p53. Inactivating mutations in p53 or increased levels of proteins that attenuate p53 activity, such as MDM2, occur in over half of all cancers. We found a compound that binds selectivity to MDM2 and releases its control of p53, allowing it to exert its anti-tumor effects, and ultimately causing cancer cells to die. This compound is currently in clinical trials Phase II.
"Knowing that our molecules can potentially help patients is very motivating"
Dr. Ralph Neumüller. Head of Cancer Cell Signaling.
"We're excited to partner with brillant teams to explore novel thereapeutics for patients."
Dr. Mark Pearson. Head of Cancer Pharmacology.
"We're a tight community working together to discover novel treatments for cancer patients."
Dr. Paola Martinelli. Assoc. Scientific Director Discovery Research.
"We're excitedto work with Boehringer to develop new therapeutic approaches to cancer."
Dr. Jean Engela. CEO NBE Therapeutics.
"We're working hard with our partners and the preclinical team to maximize opportunities fpr patients in need."
Dr. Flavio Solca. Head of Late Stage Cancer Research.
Collaboration is key
Our oncology research approaches are carried out in collaboration with the world’s academic leaders. We are proud of a growing network of collaborators who are also dedicated to making a big difference in the lives of patients. For example, in collaboration with the group led by Piro Lito at the Memorial Sloan Kettering Cancer Center (MSKCC) in the US, we have profiled an inhibitor that inactivates common KRAS oncoproteins, without the need for covalent binding to a specific mutated residue. Furthermore, with Alessio Ciulli and his team at the Center for Targeted Protein Degradation of the University of Dundee, we are investigating how Proteolysis Targeting Chimeras (PROTACs) can be used to address challenging drug targets including KRAS and transcriptional activator belonging to the SWI/SNF family of chromatin remodeling proteins (SMARCA). Additional academic collaborations include, among others, scientists at the Dana Faber Cancer Institute, Vanderbilt University, as well as preclinical and clinical researchers at the MD Anderson Cancer Center.
Publications
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Popow J, Farnaby W, Gollner A, Kofink C, Fischer G, Wurm M, Zollman D, Wijaya A, Mischerikow N, Hasenoehrl C, Prokofeva P, Arnhof H, Arce-Solano S, Bell S, Boeck G, Diers E, Frost AB, Goodwin-Tindall J, Karolyi-Oezguer J, Khan S, Klawatsch T, Koegl M, Kousek R, Kratochvil B, Kropatsch K, Lauber AA, McLennan R, Olt S, Peter D, Petermann O, Roessler V, Stolt-Bergner P, Strack P, Strauss E, Trainor N, Vetma V, Whitworth C, Zhong S, Quant J, Weinstabl H, Kuster B, Ettmayer P, Ciulli A. Targeting cancer with small-molecule pan-KRAS degraders. Science. 2024 Sep 20;385(6715):1338-1347. doi: 10.1126/science.adm8684.
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Gollner A, Rudolph D, Weyer-Czernilofsky U, Baumgartinger R, Jung P, Weinstabl H, Ramharter J, Grempler R, Quant J, Rinnenthal J, Pérez Pitarch A, Golubovic B, Gerlach D, Bader G, Wetzel K, Otto S, Mandl C, Boehmelt G, McConnell DB, Kraut N, Sini P. Discovery and Characterization of Brigimadlin, a Novel and Highly Potent MDM2-p53 Antagonist Suitable for Intermittent Dose Schedules. Mol Cancer Ther. 2024 Sep 11. doi: 10.1158/1535-7163.MCT-23-0783.
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Wilding B, Woelflingseder L, Baum A, Chylinski K, Vainorius G, Gibson N, Waizenegger IC, Gerlach D, Augsten M, Spreitzer F, Shirai Y, Ikegami M, Tilandyova S, Scharn D, Pearson MA, Popow J, Obenauf AC, Yamamoto N, Kondo S, Opdam FL, Bruining A, Kohsaka S, Kraut N, Heymach JV, Solca F, Neumuller RA. Zongertinib (BI 1810631), an irreversible HER2 TKI, spares EGFR signaling and improves therapeutic response in preclinical models and patients with HER2-driven cancers. Cancer Discov. 2024 Sep 9. doi: 10.1158/2159-8290.CD-24-0306.
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Thatikonda V, Lyu H, Jurado S, Kostyrko K, Bristow CA, Albrecht C, Alpar D, Arnhof H, Bergner O, Bosch K, Feng N, Gao S, Gerlach D, Gmachl M, Hinkel M, Lieb S, Jeschko A, Machado AA, Madensky T, Marszalek ED, Mahendra M, Melo-Zainzinger G, Molkentine JM, Jaeger PA, Peng DH, Schenk RL, Sorokin A, Strauss S, Trapani F, Kopetz S, Vellano CP, Petronczki M, Kraut N, Heffernan TP, Marszalek JR, Pearson M, Waizenegger IC, Hofmann MH. Co-targeting SOS1 enhances the antitumor effects of KRASG12C inhibitors by addressing intrinsic and acquired resistance. Nat Cancer. 2024 Sep;5(9):1352-1370. doi: 10.1038/s43018-024-00800-6.
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Kim D, Herdeis L, Rudolph D, Zhao Y, Böttcher J, Vides A, Ayala-Santos CI, Pourfarjam Y, Cuevas-Navarro A, Xue JY, Mantoulidis A, Bröker J, Wunberg T, Schaaf O, Popow J, Wolkerstorfer B, Kropatsch KG, Qu R, de Stanchina E, Sang B, Li C, McConnell DB, Kraut N, Lito P. Pan-KRAS inhibitor disables oncogenic signalling and tumour growth. Nature. 2023 Jul;619(7968):160-166. doi: 10.1038/s41586-023-06123-3.
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