PI3K inhibitors: decades of partnership between ICR researchers and industry leads to a new class of cancer drugs

We share the story of a pioneering and collaborative research programme at the ICR, initiated in the late 1990s, that led to one of the first clinical-stage PI3K inhibitors, laying the foundation for a new class of targeted drugs now benefiting cancer patients worldwide.

Image: breast cancer cells. Credit: Luke Henry

Major trial results presented at the American Society for Clinical Oncology (ASCO) 2025 meeting have confirmed the potential of Roche's drug inavolisib in patients with breast cancer. Read on for the story of the discovery and development of these pioneering cancer drugs.

Phosphatidylinositol 3-kinase (PI3K) is a lipid signalling enzyme implicated in a wide range of cancers. In 2004, researchers identified faults in the PIK3CA gene, which encodes the catalytic subunit of PI3K, in human cancer. The mutations cause the PI3K lipid signalling activity to be always switched on, resulting in cancer. Since then, PIK3CA faults have been found in several cancers, including bowel, brain, breast, stomach and lung – occurring in up to one-third of some tumour types.

“We launched our collaborative PI3K drug discovery programme, recognising the importance of this pathway even before PIK3CA mutations were first identified,” says Professor Paul Workman, Harrap Professor of Pharmacology and Therapeutics at the ICR and former Director of the then Cancer Research UK Cancer Therapeutics Unit (now the Centre for Cancer Drug Discovery (CCDD)) at the ICR. “We were right at the forefront of the field – this was truly pioneering research.”

What followed was a closely integrated effort between the ICR, academic collaborators and various companies, leading to the discovery and development of multiple drug candidates. In fact, the collaborative team discovered one of the very first PI3K inhibitors to enter clinical trials worldwide. Working closely with industry and The Royal Marsden NHS Foundation Trust, our researchers also played a leading role in some of the pivotal clinical trials for this new class of targeted cancer drugs, and laid the foundations for many PI3K drugs which followed.

By March 2024, The US Food and Drug Administration (FDA) had approved five class I PI3K inhibitors currently in clinical use for treating leukaemia, lymphoma, and some types of breast cancer. Most recently, a PI3K drug called inavolisib was approved as part of a triple combination therapy for certain patients with advanced breast cancer.

“At times, it’s been a rollercoaster,” says Workman. “But I’m hugely proud of the role we played and delighted for the success and the benefits for patients – and also excited about the future. There’s still enormous additional potential in these drugs, as PIK3CA mutations are found in many other cancer types as well.”

Early drug discovery

The story begins in 1999 with a collaboration between molecular biologists who had undertaken pivotal research on PI3Ks, Professor Mike Waterfield of the Ludwig Institute for Cancer Research at UCL and Professor Peter Parker, at the then Cancer Research UK London Research Institute (now the Francis Crick Institute) who teamed up with drug hunter Workman at the ICR with the aim to discover PI3K inhibitors.

The team gathered at the ICR’s laboratories to kick off the collaboration. “I remember it vividly, our lively conversations and how excited we were about the potential for us to discover PI3K inhibitors to treat cancer patients with an activated PI3K pathway,” reflects Workman.

Working initially with the Japanese pharma company Yamanouchi (now Astellas) under a collaboration between the Ludwig Institute for Cancer Research, Cancer Research UK, the ICR and the company, the researchers discovered several series of potent and selective class I PI3K inhibitors, some of which also inhibited the related cancer target mTOR. One of the key small molecule compounds that emerged from these efforts was PI-103, a potent inhibitor of all four members of the class I PI3K family – alpha, beta, gamma and delta – plus mTOR. “It proved to be a powerful chemical tool, allowing us to further validate the approach and demonstrate activity in mouse models that we were on the right path towards developing a drug,” says Workman.

These early collaborations were established and supported with the help of the ICR’s Business and Innovation Office, which oversees our commercial and academic partnerships, as well as Cancer Research Technology, which is now called Cancer Research Horizons – the innovation arm of Cancer Research UK, which in turn was a funder of the research at the ICR.

“In the early days of PI3K inhibitor development, the priority was to ensure seamless and smooth collaboration, while still making sure we capturing and protecting key intellectual property throughout that process,” explains Dr Jon Wilkinson, Director of our Business and Innovation Office.

In 2001, Yamanouchi exited the collaboration. But two years later, Workman, Waterfield and Parker founded the biotech spin-out company Piramed Pharma, to which the ICR, Cancer Research Horizons and Ludwig licensed research-related rights, and which then further collaborated with the ICR under a tripartite collaboration agreement between Piramed, ICR and Cancer Research Horizons.

This ICR-Cancer Research Horizons-Piramed collaboration culminated in the discovery of GDC-0941, later renamed pictilisib, a promising oral class I PI3K inhibitor for the treatment of cancer, with Professor Steven Shuttleworth – then Director of Chemistry at Piramed – leading the medicinal chemistry.

Recognising the strength of the preclinical data for pictilisib and productive partnership with ICR researchers, Piramed began exploring further licensing opportunities.

“We wanted to put Piramed on the map as a leading PI3K company – and to expedite the programme to get these drugs into clinical trials as quickly as possible,” explains Dr Khatereh Ahmadi, then Head of Business Development at Piramed. “There was a huge amount of interest – it was a hot target in cancer, and we were recognised as pioneers in PI3K inhibitors.”

In 2005, Piramed licensed its PI3K inhibitors focusing on the alpha form to Genentech for use in cancer, in a $230 million deal – one of the largest preclinical collaborations ever signed by a UK biotech company. In 2008, Piramed was acquired by Roche in a $175 million deal to develop PI3K delta inhibitors for inflammatory diseases.

“It was a real success story for UK biotech,” enthuses Ahmadi. “Piramed was a small but dynamic company, and it was an incredible journey.”

Entering the clinic

Genentech (later acquired by Roche) took on the clinical development of pictilisib, providing the resources to advance the drug into early clinical trials while continuing to work closely with ICR researchers. The company also worked with Professor Johann de Bono of the Drug Development Unit at the ICR and Royal Marsden, who led the first-in-human phase I study, providing safety data and early evidence of anti-tumour activity.

Bridging the gap between the laboratory to the clinic, Workman’s colleagues performed biomarker assays that confirmed the drug was effectively inhibiting its target in patients’ tumours and helped determine the best dose and treatment schedule.

“That was a champagne moment,” says Workman. “It was a wonderful feeling – and seeing the trial take place at the ICR and Royal Marsden was like a dream come true. It was especially pleasing that the trial followed the Pharmacological Audit Trail approach that we pioneered at ICR and used biomarkers to provide clear evidence of inhibiting the PI3K target in patients, resulting in the first clinical responses to the drug at doses that were well-tolerated. That was truly rewarding.”

Pictilisib subsequently demonstrated proof-of-concept in phase II studies in breast and other cancers, but its development was ultimately halted due to unacceptable side effects.

However, the ICR-Piramed-Genentech programme paved the way for the discovery of many other promising PI3K inhibitors, many of which progressed into clinical trials

“It was a fantastic collaboration, everyone worked so well together,” reflects Lori Friedman, then Head of Translational Oncology for Genentech Research and Early Development. “With each drug candidate that entered the clinic, we gained valuable insights into how to achieve the right balance between activity and safety.”

Beyond its role in drug development, pictilisib has also been made available to scientists around the world as a tool compound for biomedical research. It is recommended as a high-quality ‘chemical probe’ for class I PI3 kinases on the Chemical Probes Portal, helping to further advance understanding of the PI3K signalling pathway and its role in cancer and other diseases.

Image: ICR researcher Rachel Cooley in our Centre for Cancer Drug Discovery

Triple combination therapy

The next chapter of the story begins with another drug discovery screening programme by Genentech, which identified a novel chemical series of PI3K inhibitors with unique properties.

“They not only blocked the activity of PI3K alpha but also triggered the breakdown of the mutated PI3K alpha protein, effectively destroying it – a process known as targeted protein degradation,” explains Friedman. This is a major advantage over pictilisib and other inhibitors since the mutant, cancer-driving alpha form of PI3K is eliminated, whereas the normal alpha form in healthy tissues is spared. This reduces the major side-effect of increased blood glucose that is caused by inhibition of this normal form by previous drugs.

“You’re essentially targeting the key aspects of the biology of these cancers,” explains Turner. “They’re driven by hormones, they rely on CDK4/6 to initiate the cell cycle, and PI3K signalling is also crucial for their growth. If you can target all three together, it’s a far more effective approach than just inhibiting one or two aspects.”

In 2021, Turner led a phase Ib clinical trial that provided key proof of concept for this triple combination therapy. The study tested one of Roche’s new PI3K inhibitors – taselisib – with palbociclib, and hormone therapy in patients with PIK3CA-mutated hormone-receptor-positive, human epidermal growth factor receptor 2 negative (HER2-) breast cancer.

While the results showed some promise, taselisib was ultimately not the right PI3K inhibitor for the triple combination therapy.

However, from the same series of compounds, another drug candidate had emerged, inavolisib, a highly potent and selective inhibitor of PI3K alpha and degrader of mutant PI3K alpha.

In 2024, the results of an international phase III INAVO120 trial, led by Turner, demonstrated that a combination of inavolisib, palbociclib and hormone therapy, doubled the length of time before PIK3CA-mutated advanced breast cancer progressed. As a result, the new therapy combination has received FDA approval and it is hoped it will become the standard of care for women with this form of the disease.

“It felt amazing,” says Friedman. “I worked on this programme for 14 years – and getting a drug approved is a huge achievement because it represents a real advancement for patients.”

Far-reaching impact

The pioneering drug discovery, chemical biology and clinical development research led by ICR researchers in collaboration with several industry partners and part funded by Cancer Research UK, has had a profound impact on the pharmaceutical industry. A recent analysis of clinical trial data revealed that, over the past 11 years, 50 PI3K inhibitors have been tested for cancer treatment across 527 studies – a testament to the huge level of interest in targeting this pathway.

Reflecting on this progress, Workman expresses his pride in the collective effort behind these advancements.

“I’m really thrilled – it’s incredible to look back and see how far we’ve come since we first started our PI3K research back in 1999,” he says. “I’m hugely proud of everyone who has contributed to our extraordinary 25-year journey. You could in a way call it a single team, but it’s an enormous one – from the fundamental molecular biology researchers and our academic drug discovery team to our industry partners, clinicians, charity, venture capital and pharma funders, and also the business development experts who helped us do the deals that accelerated our progress. And, of course, none of this would have been possible without the patients who volunteered to take part in the clinical trials.”

“It’s a fantastic example of what the ICR and The Royal Marsden can achieve through commercialisation and collaboration with industry,” he explains.

“The story of the discovery and development of PI3K inhibitors is one of pioneering science, but it also exemplifies the full spectrum of university and charity commercialisation and technology transfer – early-stage collaboration, forming a spinout company, licensing, and hosting clinical trials in partnership with pharma.

"The most important thing is to see our discoveries benefiting patients through the development of new cancer treatments, and this is a great example of that – but it’s also a powerful story of how research institutions like the ICR generate economic impact from their discoveries, too.”