Combining two precision medicines can treat drug-resistant cancers


Date:
September 14, 2020
Source:
Institute of Cancer Research
Summary:
Launching a dual-pronged attack on tumours using a combination
of two innovative precision medicines could treat patients with
multiple common cancers, a new clinical trial shows.



FULL STORY ========================================================================== Launching a dual-pronged attack on tumours using a combination of two innovative precision medicines could treat patients with multiple common cancers, a new clinical trial shows.


==========================================================================
It is the first trial to use the pioneering genetically targeted drug
olaparib -- already licensed for ovarian, breast and prostate cancer -- together with a promising new medicine, called capivasertib.

The researchers used the drug combination to target two fundamental
weaknesses in cancer at the same time -- a damaged system for repairing
DNA, and 'addiction' to a molecule called AKT which fuels tumour growth.

The early-stage trial, led by a team at The Institute of Cancer Research, London, and The Royal Marsden NHS Foundation Trust, found that the drug combination was safe, successfully hit its targets, and was effective
against a variety of advanced cancers -- including those that had stopped responding to chemotherapy.

This combination is now planned to move forward into larger-scale
trials. The study was published in the journal Cancer Discovery.

The Institute of Cancer Research (ICR) played a key role in pioneering
both of the two precision medicines in the combination -- discovering how
to genetically target olaparib, and collaborating to create a precursor
to capivasertib before the drug's ultimate formulation by AstraZeneca.



==========================================================================
The new study is an exemplar of the research the ICR will be doing in
its revolutionary new Centre for Cancer Drug Discovery, which aims to
use combination treatments to cut off cancer's evolutionary pathways
and overcome drug resistance.

In the phase I trial, researchers gave 64 patients with advanced solid
tumours -- including those with breast cancer, ovarian cancer and prostate cancers - combinations of olaparib and capivasertib.

The combination was well tolerated, and 25 of the 56 patients whose
response could be assessed -- or 45 per cent -- benefited from treatment,
with their tumours either shrinking or stopping growing.

Some of these patients had previously stopped responding to chemotherapy
and other targeted treatments as their cancers became drug resistant.

Many of the patients who responded to the treatment had mutations to
genes involved in repairing DNA, including to the BRCA genes.



==========================================================================
The trial was funded by the pharmaceutical company AstraZeneca, under
the auspices of the Cancer Research UK Experimental Cancer Medicine
Centre Combinations Alliance.

The findings provide early clinical evidence that olaparib and
capivasertib have the potential to work well as a combination treatment
and could improve outcomes for some patients with drug-resistant cancer.

The team are now planning further, later-stage clinical trials to assess
the drug combination's benefit and to study its effect in patients whose tumours do not have faults in the AKT gene or related to DNA repair.

The ICR is the most successful academic institution in the world at
discovering cancer drugs -- having discovered 20 new drug candidates
since 2005. The ICR is nearing completion of a new Centre for Cancer Drug Discovery, and is now raising money for the state-of-the-art equipment
its scientists will need to get their work in the building off to the
strongest possible start.

Study leader Professor Johann de Bono, Professor of Experimental Cancer Medicine at The Institute of Cancer Research, London, and Consultant
Medical Oncologist at The Royal Marsden NHS Foundation Trust, said:
"Our study establishes the potential of a combination of two precision medicines for patients whose tumours have stopped responding to existing
drugs.

The combination of olaparib and capivasertib works by attacking two
fundamental weaknesses in cancer, and could potentially be used to
treat patients with several common tumours. I look forward to seeing
the possible benefit of the combination tested in later-stage trials." Professor Paul Workman, Chief Executive of The Institute of Cancer
Research, London, said: "This new clinical trial is a terrific example
of how we can now translate scientific discoveries about the biology of
cancer cells into innovative new cancer treatments with real benefits
for patients. It's also an example of the pioneering strategy we have
adopted at the ICR of targeting cancer evolution and drug resistance --
often through the use of combination treatments to hit multiple targets at
once and block off escape routes, just as is done with diseases like HIV.

"It's very exciting to see two drugs pioneered thanks to the ICR's
research now being used together in patients, with the real possibility
that they could offer an urgently needed new treatment option for patients whose cancers have become resistant to current treatments."

========================================================================== Story Source: Materials provided by Institute_of_Cancer_Research. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Timothy A. Yap, Rebecca Kristeleit, Vasiliki Michalarea, Stephen J.

Pettitt, Joline S.J. Lim, Suzanne Carreira, Desamparados Roda,
Rowan Miller, Ruth Riisnaes, Susana Miranda, Ines Figueiredo,
Daniel Nava Rodrigues, Sarah Ward, Ruth Matthews, Mona Parmar,
Alison Turner, Nina Tunariu, Neha Chopra, Heidrun Gevensleben,
Nicholas C. Turner, Ruth Ruddle, Florence I. Raynaud, Shaun A
Decordova, Karen E Swales, Laura Finneran, Emma Hall, Paul Rugman,
Justin P O Lindemann, Andrew Foxley, Christopher J. Lord, Udai
Banerji, Ruth Plummer, Bristi Basu, Juanita S Lopez, Yvette Drew,
Johann S. de Bono. Phase I trial of the poly(ADP- ribose) polymerase
(PARP) inhibitor olaparib and AKT inhibitor capivasertib in patients
with BRCA1/2 and non-BRCA1/2 mutant cancers.

Cancer Discovery, 2020; CD-20-0163 DOI: 10.1158/2159-8290.CD-20-0163 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/09/200914194027.htm

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