Cancer drug discovery at Newcastle University has been in progress for three decades. The previous Cancer Research UK Programme was co-directed by Professor Herbie Newell and Professor Roger Griffin. Professor Newell was also Director of Translational Research at Cancer Research UK from 2006 – 2009 and interim Executive Director of Clinical and Translational Research in 2007-2008. He was awarded a CBE for services to Medical Research and Drug Development in the Queen’s 2019 New Year Honours and is currently Emeritus Professor of Cancer Therapeutics at Newcastle University, having retired in 2016. Professor Griffin was awarded the Royal Society of Chemistry’s George and Christine Sosnovsky Award in Cancer Therapy in 2014.

Professors Herbie Newell (left) and Roger Griffin (right)

The successful programme of research involved projects that led to the identification of two marketed drugs; the poly(ADP-ribose) polymerase (PARP) inhibitor rucaparib and the fibroblast growth factor receptor (FGFR) inhibitor erdafitinib (JNJ-42756493).

Approved medicines:

Rucaparib (PARP1 inhibitor)

Newcastle independently established a project to identify the first PARP inhibitors, then forged a collaboration with industry (Agouron Pharmaceuticals and Pfizer) to discover the PARP inhibitor rucaparib, which is now marketed as Rubraca®. 

Newcastle independently established a project to identify the first PARP inhibitors, then forged a collaboration with industry (Agouron Pharmaceuticals and Pfizer) to discover the PARP inhibitor rucaparib, which is now marketed as Rubraca®.

Rucaparib entered the clinic in 2003, in Cancer Research UK-sponsored Phase I trials in Newcastle (PI Professor Ruth Plummer), representing the first administration of a PARP inhibitor to a cancer patient worldwide. Independent research conducted by Sheffield/Newcastle and Cambridge/ICR subsequently revealed a synthetic lethal interaction between PARP inhibition and homologous recombination DNA repair-deficiency, providing a basis for its examination in BRCA mutated (germline and/or somatic) cancers, through a clinical development programme supported by Clovis Oncology. 

Rubraca is now approved in two different indications in ovarian cancer:

• The maintenance treatment of adults with ovarian cancer, fallopian tube cancer, or primary peritoneal cancer whose cancer has come back and who are in response (complete or partial response) to a platinum-based chemotherapy.
• The treatment of adults with ovarian cancer, fallopian tube cancer, or primary peritoneal cancer who have certain “BRCA” gene mutations, either inherited (germline) or acquired (somatic), and who have been treated with 2 or more chemotherapy medicines for their cancer.

The Newcastle Cancer Centre was awarded the inaugural Cancer Research UK Translational Research Team Prize in 2010 for this work, which combined basic, translational, drug discovery and clinical science contributions.

Erdafitinib (FGFR inhibitor)

The Newcastle DDU pursued the idea of developing a selective FGFR tyrosine kinase inhibitor and established a single-project collaboration with Astex Pharmaceuticals for this purpose, leading to the discovery of compounds that were shown to have very significant antitumour activity in FGF/FGFR-dependent tumour models. The inhibitors formed the basis of a further collaboration between Astex and Janssen, resulting in the clinical development candidate, erdafitinib (JNJ-42756493).

In April 2019, erdafitinib became the first FGFR tyrosine kinase inhibitor to receive an FDA (USA) approval in patients with locally advanced and unresectable or metastatic urothelial cancer that harboured aberrant forms of FGFR-2 or -3, and who had previously progressed on at least one line of platinum-containing chemotherapy. The compound is now marketed by Janssen as Balversa^TM.

Candidate drugs in early clinical evaluation:

The Cancer Research UK Newcastle Drug Discovery Unit has also initiated two other projects that have led to the identification of candidate drugs that are currently being evaluated in early clinical trials.

ASTX295 (MDM2-p53 antagonist)

A Newcastle MDM2-p53 antagonist project was one of the first projects to be accepted into our Drug Discovery Alliance with Astex Pharmaceuticals (UK). Newcastle structurally-enabled the project, enabling significant potency gains to be realised. Significant additional investment by Astex enabled the joint project team to deliver a candidate molecule (ASTX295) which entered Phase I/II clinical development in July 2019. The compound is being examined in patients with wild-type-TP53 tumours.

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