Preclinical Evaluation of Rational Drug Combinations with BH3 mimetics in Colorectal and Small Cell Lung Cancer

Abstract

AbstractAbstract of a thesis entitled "Preclinical evaluation of rational drugcombinations with BH3 mimetics in colorectal and small cell lung cancers,"submitted by Danielle Potter for the degree of Doctor of Philosophy (PhD) to TheUniversity of Manchester, September 2015Colorectal (CRC) and small cell lung cancer (SCLC) are among the most commoncancers and are leading causes of cancer related deaths worldwide. Prognosis ispoor for both metastatic CRC (mCRC) and SCLC patients for reasons includingeligibility for curative surgery, late diagnosis and limited treatment options. Fiveyear survival rates of patients with mCRC or extensive stage SCLC are 5% and2% respectively.Standard of care (SOC) for mCRC is based on multiple chemotherapy regimenswhilst more recently introduced targeted therapies such as Bevacizumab andCetuximab have only improved survival of mCRC patients by 1.5-2.6 months. SOCfor SCLC patients is platinum based chemotherapy +/- radiation whereby themajority are initially chemo-sensitive followed by an inevitable chemotherapyresistantrelapse within 3-18 months. In both mCRC and SCLC, diseaseprogression is largely due to a high degree of tumour heterogeneity andinnate/acquired resistance to therapy due to multiple mutations in non-redundantpathways. As such treatment for both mCRC and SCLC has made little progressin 30 years resulting in a clear unmet need to improve current/develop newtherapies for these patients.Several hallmarks of cancer including sustained proliferation and resistance to celldeath implicate Phosphoinositide 3-kinase (PI3K) signaling, frequently deregulatedin both CRC and SCLC whilst anti-apoptotic proteins including Bcl-2 familymembers are commonly upregulated in all cancers. The rational drug combinationof a PI3K inhibitor (PI3Ki; PI-103 or GDC-0941) and a Bcl-2 family targeted BH3mimetic (ABT-737 or Navitoclax) was investigated in preclinical CRC and SCLCmodels. ABT-737 and Navitoclax directly interacts with the anti-apoptotic proteins,BCL-2, BCL-xL and BCL-w antagonising their interactions with pro-apoptotic, BH3-only proteins and effector proteins to induce apoptosis. The findings of this thesisconfirm that combining ABT-737 with PI-103 increases the potency of ABT-737 invitro in CRC and SCLC and the GDC-0941/Navitoclax combination improvedoverall survival of mice bearing human SCLC tumours compared to either drug asa single agent and to SCLC SOC. For the first time the Tec kinase BMX was alsoimplicated in the observed responses to this combination.Novel therapies are usually tested in combination with SOC in mCRC and SCLCpatients. The BH3 profiling technique can determine how "primed‟ a tumour cell isfor apoptosis and reports mitochondrial outer membrane permeabilization (MOMP)after treatment with BH3 peptides. BH3 profiling was optimised for SCLC CTC(circulating tumour cell) Derived eXplants (CDX) models and the approach wasvalidated retrospectively on chemo-sensitive and chemo-refractory CDX. Finally,prospective BH3 profiling was able to predict responses to SOC chemotherapy inpaired CDX models derived from chemotherapy-naïve patients and again atrelapse with disease progression. The overall conclusions from this thesis are (i)use of PI3K inhibitors and BH3 mimetics in combination should be tested in theclinic, particularly in SCLC, (ii) BH3 profiling should be optimised as a CTC assayto predict chemotherapy responses in SCLC.

Date of Award	31 Dec 2015
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Caroline Dive (Supervisor) & Christopher Morrow (Supervisor)