Authors

D Howard¹; K Edwards¹; D James¹; K Murphy²; S Rex²; K Lutchman-Singh²; L Margarit³; J Worthington⁴; N Williams⁴; N Al Kafri¹; B Pan-Castillo¹; S Munckley¹; M Bilbao-Asensio¹; S Michue-Seijas¹; P Rees¹; L Francis¹; D Gonzalez¹; RS Conlan¹; 
¹ Swansea University, UK;  ² Swansea Bay University Health Board, UK;  ³ Cwm Taf Morgannwg University Health Board, UK;  ⁴ Axis Bioservices Ltd., UK

Discussion

Gynaecological Cancers are some of the most common and deadly cancers in women. Endometrial Cancer (EC) is the fourth most common cancer in women in the UK and while prognosis is generally positive (5-year survival: 80 %), the more aggressive, hormone receptor negative, Type II EC is far deadlier (5-year survival: 55 %). Ovarian Cancer (OC), due largely to late diagnosis and chemo-resistance, is the deadliest of the gynaecological cancers and has a 5-year survival rate of just 45%. Here we investigate the use of cyclin dependent kinase inhibitor, dinaciclib, to address the clinical need for novel therapeutics in the treatment of these cancers. Using cell lines and primary cells isolated from patient tumours, we show that dinaciclib is highly efficacious in EC, across subtypes I and II and in OC, in both platinum sensitive and resistant cells. We demonstrate that dinaciclib operates via a bimodal mechanism inhibiting transcription and causing cell cycle arrest.

Our results add to the growing body of preclinical work demonstrating the efficacy of dinaciclib in numerous cancer types. Nonetheless, dinaciclib has failed to advance through clinical trials in solid tumours, which we speculate is largely attributable to its short half-life and off-target effects that limit its dose. We are therefore developing drug delivery tools designed to increase its circulation, enhance accumulation in the tumour and protect against off-target effects. Here we show early results of two dinaciclib encapsulating polymeric nanoparticles. These particles show efficacy in OC cell lines of platinum-resistant and sensitive cancer in both adherent and spheroid cultures. While results are preliminary, we believe that advanced drug delivery systems, such as those designed in our group, have an important role to play in exploiting the therapeutic potential of our small molecule arsenal.