New cancer treatment targets genetic mutations with targeted drugs

A new approach to cancer treatment is showing remarkable promise in targeting even the most aggressive tumours. The method involves identifying the specific genetic mutation driving a patient's cancer, allowing doctors to prescribe targeted drugs that can switch off the mutated gene.

This precision oncology approach has already saved the life of Stephen Huff, a 29-year-old former professional baseball player who was diagnosed with stage 4 lung cancer after experiencing shortness of breath. Despite his young age and fit lifestyle, Huff's scan revealed multiple tumours throughout his body, including in his lungs, neck, spine, liver, and brain.

Huff's mother, a cancer researcher, encouraged him to try this new approach, which focuses on genes rather than the location of the original tumour. This led to a targeted treatment plan that prescribed a recently approved drug specifically designed to tackle the genetic alteration driving Huff's cancer.

The results were nothing short of miraculous: within weeks, Huff began to feel better, and his first scan showed significant shrinkage or complete disappearance of every tumour site. Thanks to this precision oncology method, more people like Huff are surviving cancers that were once considered incurable, including lung, pancreatic, and brain cancer.

David Thomas, a pioneer in the field of precision oncology at the University of New South Wales in Sydney, says that being able to identify exactly what makes a cancer tick has had an incredible impact. However, surprisingly, this revolutionary approach has received little attention outside of the medical community so far.

The traditional method of discovering new cancer drugs involved chance and trial-and-error. For example, the chemotherapy drug cisplatin was stumbled upon by scientists experimenting with platinum electrodes and bacteria in the 1960s, while another widely used drug, paclitaxel, was isolated from the bark of the Pacific yew tree through random screening of plant extracts.

This new approach is a significant departure from the old way of doing things, but it's clear that precision oncology has already made a major difference in the lives of patients like Stephen Huff.

This new approach is built on the understanding that cancer is not just a disease of specific tissues or organs, but rather a genetic condition that can affect anyone regardless of their background.

The traditional method of treating cancer often involves using broad-spectrum chemotherapy drugs that target rapidly dividing cells in general, without considering the unique characteristics of each individual's tumour.

This approach has its limitations, as it can cause significant side effects and still fail to eliminate all cancer cells, leaving some hiding in deep within the body's tissues.

In contrast, precision oncology takes a more targeted approach by identifying the specific genetic mutations driving a person's cancer, rather than relying on broad anatomical classifications or cellular appearances under a microscope.

For instance, in the case of non-small cell lung cancer, which is characterised by large cells that can be identified under a microscope, researchers have identified certain genetic mutations that are more common in this type of cancer.

One such mutation involves a gene called EGFR, which has been shown to play a role in the development of some lung cancers.

Similarly, other genes like BCR and ABL1 have been linked to chronic myeloid leukaemia, a blood cancer, and scientists have developed targeted drugs that can block the abnormal proteins produced by these mutations.

The first breakthroughs in precision oncology date back to the 1990s and early 2000s, when researchers identified specific genes associated with certain types of cancer.

The test used to identify specific genetic alterations in tumours has been refined over time, allowing for more precise targeting of cancer cells.

This approach, known as comprehensive genomic profiling, examines multiple genes at once to pinpoint the underlying cause of a patient's cancer.

In one notable case, a patient underwent a biopsy that looked at over 300 genes in a single sample of his tumour tissue.

The results revealed an alteration in the ALK gene, which is involved in cell growth and division, indicating that his cancer was being driven by this specific genetic change.

This information allowed doctors to recommend a targeted treatment, specifically a drug called alectinib, which targets the ALK gene mutation.

One of the pioneering trials of comprehensive genomic profiling was launched by the Garvan Institute of Medical Research in Sydney in 2016.

The trial enrolled almost 4000 participants with advanced cancers that had exhausted all available treatment options, including lung, pancreatic, brain, ovarian, bowel, and breast cancer patients.

The results of a groundbreaking trial have shown that patients with pancreatic cancer can now expect a significantly improved prognosis when treated with targeted therapy. According to data from the study, nearly 30% of individuals who receive a recommended treatment are still alive five years after diagnosis, compared to just 4% of those without a match.

This substantial increase in survival rates is largely due to the ability of precision oncology testing to identify patients who would benefit from immunotherapy drugs known as checkpoint inhibitors. These medications effectively neutralize the cancer cells' ability to evade the immune system by disarming its defenses.

A new development has further bolstered hopes for pancreatic cancer patients, with the recent approval in the US of a drug called daraxonrasib. This medication targets mutations in the KRAS gene, which are common in this type of cancer and often prove resistant to standard treatments.

Studies have shown that daraxonrasib can double the survival time of individuals with advanced pancreatic cancer, offering new hope for those who had exhausted all other options. The approval of this drug marks a significant milestone in the fight against this aggressive form of cancer.

Another malignancy that has long been considered particularly challenging is brain cancer, but researchers are now making headway with targeted treatments. A new medication called vorasidenib has shown promise in clinical trials by targeting mutations in genes known as IDH1 and IDH2.

These genetic alterations often trigger the growth of gliomas, a type of brain tumor that can be particularly aggressive and difficult to treat. In one trial, patients who received vorasidenib experienced a significant reduction in cancer progression compared to those given a placebo, with 61% fewer individuals experiencing worsening symptoms during the study period.

Several countries are now incorporating comprehensive genomic profiling into their public healthcare systems, providing patients with advanced cancers access to targeted treatments tailored to their specific genetic profiles. Japan, Germany, Norway, and Denmark have all implemented this approach as part of their national cancer treatment plans.

In contrast, while most people in the UK are eligible for comprehensive genomic profiling through the National Health Service (NHS), the results of these tests are often limited by what is currently available on the NHS. For example, genetic alterations in the ALK gene are reported for lung cancer patients because a relevant treatment called alectinib is already approved in the UK.

The potential benefits of comprehensive genomic profiling go beyond standard care and could also facilitate recruitment into clinical trials for new treatments. According to oncologist Matthew Krebs from the University of Manchester, there remains untapped potential for identifying patients who could benefit from experimental therapies, highlighting the need for further research and investment in precision oncology.

To increase the effectiveness of precision oncology, researchers are advocating for a larger panel of "research genes to be included in genomic profiling tests. Currently, only a small number of genes are reported, and adding more could help identify patients who may benefit from experimental therapies.

In contrast to the UK's National Health Service (NHS), which has a coordinated approach to precision oncology, the US relies on a patchwork of services led by various universities and research institutes. This fragmented system can make it difficult for patients to access comprehensive genomic profiling and subsequent targeted treatments.

According to experts, one reason why only a minority of people with advanced cancer in the US undergo this testing is due to lack of awareness about its availability and benefits. Additionally, socioeconomic and geographic disparities also play a significant role in limiting access to precision oncology services.

The issue of accessibility extends beyond testing itself, as patients may struggle to obtain the targeted drugs recommended by their genomic profiles. In some cases, these medications are approved only for specific types of cancer, leaving patients to pay out-of-pocket or seek alternative options.

To address this challenge, a new approach is emerging in the form of tumour-agnostic" drugs. These medications can be prescribed for any type of cancer, regardless of its location within the body, providing greater flexibility and access for patients.

However, another concern facing precision oncology is the development of drug resistance. As targeted therapies become more effective at hitting specific genetic mutations, cancers may adapt by finding alternative pathways to grow and thrive. This necessitates the continuous development and approval of new targeted drugs.

Researchers are working to stay ahead of this challenge, as evidenced by the experiences of patients like Huff, who benefited from a newer ALK-targeted drug after his cancer developed resistance to an initial treatment.

The ambitious goal of cutting childhood cancer deaths down to zero is being tackled by a programme called Zero Childhood Cancer in Australia, which offers a more comprehensive approach compared to adult programmes.

When a child joins this programme, their entire tumour genome is sequenced, not just a few hundred genes, providing a detailed picture of the genetic mutations driving their cancer. This is followed by additional tests, including RNA whole transcriptome sequencing and methylation profiling, to further refine the understanding of the cancer's biology.

To gain even more insights, the programme also sequences the child's genome as it was at birth, in an effort to identify any predisposing factors that may have contributed to their cancer development. In some cases, cancer cells are grown in a lab for robotic testing of over 100 different drugs or in mice to assess the potential efficacy of specific treatments.

This holistic approach has yielded impressive results, including the case of Jack Kennelly, who was diagnosed with a fast-growing brain tumour at just three years old and benefited from this targeted treatment strategy. His story serves as an example of the programme's effectiveness in tackling even aggressive forms of childhood cancer.

By combining cutting-edge technology and precision medicine, programmes like Zero Childhood Cancer are pushing the boundaries of what is possible in the fight against childhood cancer, offering new hope for families affected by this devastating disease.