Title: PI3Kalpha and PI3Kdelta in cancer biology and therapy
Funder: Cancer Research UK

Abstract: BACKGROUND – Most solid tumours demonstrate genetic PI3K-activation. However, the clinical impact of PI3K-inhibitors, aimed at dampening cancer-cell-intrinsic PI3K kinase-activity, has been limited. Evidence now indicates that the clinical-efficacy of PI3K-inhibition can also derive from: •interrupting the cancer cells’ responses to micro-environmental stimuli, illustrated by the approved PI3Kdelta-inhibitor idelalisib in B-cell malignancies. •stimulation of host anti-tumour immune-responses by inhibiting leukocyte-specific PI3K-isoforms such as PI3Kdelta, a concept currently being tested in clinical trials, including by CRUK. AIMS - To understand the cancer-cell-intrinsic and immunomodulatory roles of ubiquitously-expressed PI3Kalpha and leukocyte-restricted PI3Kdelta. 1-PI3Kalpha/PIK3CA: Genetic PIK3CA-activation causes constitutive signalling and thereby has a distinct impact than transient PI3K-stimulation by growth factors. However, due to a focus of previous PI3K-research on PI3K-inhibitor studies and acute growth-factor signalling, this difference remains poorly understood. We propose to: •uncover and molecularly dissect the events induced early upon genetic PIK3CA-activation, focusing on, but not limited to, the impact on microtubules/centrosomes/chromosome dynamics. •test whether PIK3CA-activation can drive chromosomal instability. •explore whether this knowledge can be exploited therapeutically, e.g. in reducing cancer-cell heterogeneity or in optimizing microtubule/centrosome-based PI3K-combination-therapies. Oncogenes/tumour-suppressors affect the tumour microenvironment. We have discovered a similar function of PIK3CA-activation in benign overgrowth-syndromes, but such a role in cancer remains unknown. We will investigate the stromal consequences of PIK3CA-activation in cancer, focusing on immunomodulation and the potential for rational combination-therapy with PI3Kdelta-inhibitors. 2-PI3Kdelta/PIK3CD: We were the first to clone PIK3CD and have been instrumental in dissecting PI3Kdelta’s roles in immunity and leukaemia. PI3Kdelta-inhibitors are the most successful PI3K-inhibitors to date, being approved for B-cell malignancies and, as we discovered, with potential use in cancer-immunotherapy. Given that PI3Kdelta-inhibitor-based cancer-immunotherapy is likely to require combination treatment, we will investigate: •the involvement of dendritic cells (whose pro-inflammatory functions we found can be enhanced by PI3Kdelta-inhibition), in the context of potential use of PI3Kdelta-inhibitors in cancer-vaccination. •whether (pre)conditioning of tumours with radiotherapy or PI3Kalpha-inhibitors, which might enhance host anti-cancer immune-responses, can improve its efficacy. METHODS: mammalian cell/mouse-based models - cell-biology/signalling/genomics/proteomics/bio-informatics – immunological analysis in mouse cancer models. HOW THE RESULTS WILL BE USED - Our studies will explore how to maximize the impact of PI3K-inhibitors in the induction of cancer-cell cytotoxicity/cytostasis and beyond, including the dampening of tumour-evolution and stimulation of the host anti-cancer immune response, using rational combination of existing isoform-specific PI3K-inhibitors. We hope our laboratory-research will provide the scientific underpinning for future clinical trials, as it has done in the past.


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS;GENERIC HEALTH RELEVANCE