The Science of Cancer: Helping More Patients Become Survivors

Working in oncology isn’t just a job. It is personal. Each one of us has been touched by cancer in some way. Each one of us thinks about how many more people might be helped if we can shorten the time it takes to bring a new treatment option to patients. This is what drives our efforts to accelerate discovery and development of new approaches in cancer therapy. Because every moment counts as we endeavor to help more cancer patients become cancer survivors.  

Accelerating the Science of Cancer at Merck KGaA, Darmstadt, Germany
We focus every day on expanding the impact our therapies can have for patients, from maximizing the reach of our established standard-of-care medicines to investigating new ways to improve outcomes for people living with cancer. And as we also look to pioneer novel medicines and accelerate the development of new therapeutic approaches, we direct our scientific expertise and research efforts to the unmet needs where we can deliver the greatest impact for patients. With synergistic approaches in our pipeline that target key pathways involved in cancer cell survival, we are deploying mechanisms that hit cancer at its core—its DNA.

Taking a Precision Approach
The ability to hit cancer at its core takes more than developing new treatments. It relies on identifying the right patients likely to benefit from therapy based on their unique tumor biology. Collectively, we have made significant progress in understanding the biology of cancer, which is helping us uncover and exploit increasingly precise ways—precision medicine approaches—to defeat cancer cells. This extends into targeting specific vulnerabilities in some cancers, inhibiting certain escape mechanisms that help cancer cells survive, as well as exploiting synergies between combinations of treatments that may be beneficial to certain patients. Some of these combinations include our current standard-of-care treatments and in potential combinations with our pipeline molecules.

Targeting a Potential Vulnerability of Cancer
The inhibition of DNA damage response (DDR) is among many exciting cancer treatment approaches being investigated today, taking us directly to the core of cancer—its faulty and unrepaired DNA. Cells with defects in their DNA repair machinery fail to preserve their genetic integrity, and the accumulation of mutations and genetic instability, which represent an important cancer vulnerability, is well-recognized as a hallmark of cancer.¹  Targeting DDR defects in cancer cells represents a unique opportunity to eliminate cancer cells that can be explored in variety of clinical settings.

At Merck KGaA, Darmstadt, Germany, we are exploring three targets that are implicated in several DNA repair mechanisms: ataxia telangiectasia and RAD3-related (ATR), ataxia telangiectasia mutated (ATM), and DNA-dependent protein kinases (DNA-PK). We believe our diverse pipeline of selective and potent DDR inhibitors has the potential to deliver on the promise of this class of agents, transforming cancer care and tipping treatment balance towards cancer cell death. We already use information about the DNA repair enzymes that can predict clinical success of DDR inhibitors, yet we know we are probably only scratching the surface due to a complex interplay between the targets, the mechanisms of DNA damage and the combination approaches. There is much more research going on in this field to deepen our understanding of cancer vulnerabilities, escape mechanisms and synergies between various DNA damage pathways to improve the therapeutic impact of this new class of drugs.

Restoring Sensitivity to Apoptosis
Behind cancer’s wall of resistance to treatment is an escape mechanism allowing it to evade programmed cell death, or apoptosis. Apoptosis plays a critical role in development and the body’s normal function, eliminating any unnecessary or unwanted cells in a highly regulated process. Cancer cells learn how to evade apoptosis and thus develop resistance to the killing effect of chemotherapy or radiotherapy, contributing to disease recurrence. Restoring sensitivity to apoptosis in cancer cells therefore represents a potential opportunity to overcome this wall of resistance. We are investigating the potential of this pathway in clinical studies in locally advanced head and neck cancer. The opportunity to develop a potential therapy for these patients is quite meaningful for us, as this is an area that has not seen significant advance in treatment in the past 20 years.²

Delivering Anticancer Compounds to The Core of Cancer
Another area of our research is focusing on antibody-drug conjugate (ADC) technology that aims to improve selective delivery of anticancer therapy to cancer cells while sparing normal tissues. ADCs are specialized delivery systems consisting of three main components—antibodies, linkers, and payloads (typically a cytotoxic drug). By linking a targeted monoclonal antibody to an anti-cancer agent—the “payload”—we can optimize the features of both components. Emerging ADC technology enables the targeted, or precision, delivery of potent cytotoxic agents to cancer cells, while minimizing damage to healthy cells. A payload can be designed for stability and superior cancer cell-killing activity with a broad therapeutic window. This focused delivery of the cytotoxins directly to the cancer cells may significantly enhance the effectiveness of cancer treatment, especially when combined with other therapies.  

At Merck KGaA, Darmstadt, Germany, we have a portfolio of two clinical and nine preclinical assets in the ADC space. Our first in-house-developed ADC compound advanced into clinical development in 2022 to treat patients with colorectal cancer and other GI malignancies. This anti-CEACAM5 ADC is linked with a topoisomerase 1 inhibitor payload that has been rationally designed for stability in circulation and superior cancer cell killing activity with a broad therapeutic window. And there are  other payloads, for example immunomodulatory payloads, that can be linked with antibodies as well, broadening the potential of this class. One example is our collaboration with Mersana to leverage its proprietary Immunosynthen STING-agonist ADC platform, which was also announced in 2022. An approach that can directly target the tumor microenvironment with an immunomodulatory ADC has the potential to bring the benefits of this immunotherapy to a broader group of patients.

Accelerating The Science of Cancer
Through focused research in our areas of expertise—including DDR, ADCs, and apoptosis—we are striving to accelerate the delivery of novel therapies for patients with cancer. We are building and evolving precision medicine approaches targeting unique vulnerabilities of cancer with the aim to ultimately prolong patient survival. With these cutting-edge technologies, we may be able to develop more precise and personalized cancer treatments that could significantly improve outcomes for patients in the future. Targeted delivery of tumor DNA-damaging payloads with ADC technology, inhibition of DDR mechanisms, and restoration of sensitivity to apoptosis represent a new era in the science of cancer.

References

1  Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011 Mar 4;144(5):646-74. doi: 10.1016/j.cell.2011.02.013. PMID: 21376230

2  Denaro N, Merlano MC, Russi EGl. Follow-up in head and neck cancer: do more does it mean do better? A systematic review and our proposal based on our experience. Clin Exp Otorhinolaryngol. 2016;9(4):287-297. doi:10.21053/ceo.2015.00976

US-NONO-00407. 05/23