Executive Vice President, Oncology R&D, AstraZeneca
We start with the idea that by the time cancer is diagnosed, it has been evolving often for many years and has multiple genetic and epigenetic changes driving its growth. To achieve long-term survival and potential for cure, it must be attacked from many angles. By simultaneously developing therapies that directly target cancer cells and others that activate the immune system to help in the fight, we are exploring the next wave of treatments, including novel combinations that may result in deeper, more durable responses.
Since I first trained as an oncologist nearly 30 years ago, there has been phenomenal progress in cancer research, not least here at Oncology R&D, AstraZeneca.
We approach the development of transformational medicines in two distinct ways:
1) Mechanisms that directly kill cancer cells - e.g. by switching ‘off’ growth-driving mutations, targeting chemotherapy or radiation directly to cancer cells using antibodies, targeting key vulnerabilities in the DNA damage response and targeting epigenetic changes
2) Activating the immune system to boost the body’s natural defenses which can slow the growth of cancer cells, destroy the cells or to stop them from spreading (e.g. by overcoming immune suppression, activating existing T-cells and replacing the immune system)
Through our relentless quest for innovation, we have created one of the most diverse portfolios in the industry to tackle cancers with the greatest unmet need.
This approach is underpinned by our ability to rapidly gain a deeper understanding of disease biology and identify a wealth of potential drug targets that may hold the keys for unlocking new treatments and potential cures. We are using a multi-pronged approach – investing in genomics, data science and AI, next-generation sequencing and CRISPR gene editing – to identify, interrogate, and validate new targets in a way not previously thought possible. Each new insight and every new piece of information brings us closer to creating better, more advanced and more effective treatments for patients.
Attacking cancer from multiple angles
Developing new medicines that target cancer cell drivers and overcome resistance
The potential of antibody drug conjugates (ADCs) to improve the treatment of breast, lung, gastric and other cancers is tremendous. ADCs are exceptional cancer-killing agents that could become the new backbone in treatment combinations. Unlike conventional chemotherapy treatments, ADCs deliver a drug directly into cancer cells and limit damage to healthy ones1. In a similar way, we can use antibodies to target radiotherapy to kill cancer cells, sparing normal tissues.
We can also now create medicines that exploit the body’s multiple ways of detecting and repairing DNA damage, known as DNA damage response (DDR) mechanisms. Many cancers have lost one of these DDR mechanisms, which make them vulnerable to targeting other parts of these pathways2.Cancer cells also have incredibly high mutation rates, which results in dysfunctional cellular machinery and damaged DNA. While these cells can survive with a certain level of damage, there is a limit. Our goal is to develop innovative, targeted, and biomarker-driven treatments that exploit these vulnerabilities in the cancer cells.
However, many patients who initially respond to targeted therapies develop resistance to their treatment, causing it to stop working on cancer cells3 .That’s why we’re zeroing in on how to target the genetic mutations and mechanisms that facilitate this resistance process – including targeting multiple biological pathways simultaneously – with the potential to extend survival for patients with resistant cancers4.
Not all cancers are driven by direct changes to the genome. We’re just beginning to understand how the patterns of how different genes are expressed or suppressed in different settings – called epigenetics – can control cancer growth and even can lead to drug resistance5. We’ve launched several projects to better understand how we can use the learnings from epigenetics to design more effective treatments.
Aiming for a cure by harnessing the power of the immune system
In addition to targeting mutations and epigenetic changes in cancer, we are pioneering approaches to develop the next wave of immuno-oncology (IO) medicines. IO therapies can spur recognition of the presence of cancer that the human body’s own immune surveillance mechanisms may have missed, and can overcome the immunosuppressive mechanisms that cancers frequently develop as they evolve6,7. IO therapies have become the backbone of many cancer regimens.
Our broad pipeline features a range of potential first-in-class IO therapies across multiple tumour types that are being investigated across all stages of disease and lines of therapy, including novel combinations of IO therapies with the potential to induce deeper, more durable responses8,9.
We are also exploring ways to activate the natural T-cell response to attack cancer cells, through the development of next-generation immune engagers with potential in hard-to-treat solid tumours. T-cell engagers have one arm that binds to T-cells and another that binds to cancer cells, and thus ‘pull’ T-cells into the tumour.
The power of cell therapies to transform cancer treatment by amplifying the body's natural immune response has been one of the biggest stories in oncology over the past decade. We are investing significantly to address the limitations that exist in this space – which has the promise to put cures within reach one day.
Looking to the future
We are also looking for new ways to enhance cell therapy through combinations with other agents in our portfolio and via strategic research collaborations. Evidence suggests that targeting more than one pathway may combat multiple tumour escape mechanisms, potentially allowing for greater anti-tumour activity than with one pathway alone10,11,12, and we are exploring a number of IO combination strategies for these synergistic effects.
However, it is an unfortunate reality that many cancers are identified and diagnosed in the metastatic setting; we need to identify and treat disease earlier for optimal outcomes. We are investigating ways to detect cancer signals sooner, such as using measurements of circulating tumour DNA to identify patients who are most at risk of their cancer returning – to inform a personalised treatment strategy.
We are on the cusp of significant advances in the way we treat cancer and bringing transformative medicines to patients. By following the science, being bold, and not fearing failure, we are getting closer to our mission of offering a potential for cure for an increasing proportion of the millions of people worldwide living with cancer.