- Ruth Plummer (Newcastle upon Tyne, GB)
22IN - Overview: Multiple ways to harness targeting DNA to treat cancer
- Ruth Plummer (Newcastle upon Tyne, GB)
- Ruth Plummer (Newcastle upon Tyne, GB)
23IN - Novel topoisomerase inhibitors
- Yves Pommier (Bethesda, US)
- Yves Pommier (Bethesda, US)
Abstract
Background
DNA topoisomerases are validated targets for a broad range of widely used anticancer drugs. They include the topoisomerase II (TOP2) inhibitors, etoposide, teniposide, doxorubicin, daunorubicin and mitoxantrone, and the topoisomerase I (TOP1) inhibitors, topotecan and irinotecan. Both topotecan and irinotecan are derivatives of the plant alkaloid camptothecin. To overcome the limitations of these camptothecin derivatives (chemical instability, short half-life, resistance of cancer cells overexpressing multidrug-resistance efflux pumps and rapid reversibility of the TOP1 cleavage complexes), we have developed a different chemical series of TOP1 inhibitors, the indenoisoquinolines, which overcome the camptothecin limitations. Three indenoisoquinolines are in early clinical trials at the Center for Cancer Research of the US National Cancer Institute, LMP400 (indotecan), LMP776 (imidotecan) and LMP744. We will report on these new drugs, which are now transitioning to Phase 2 clinical trials. We also report on the determinants of response to the TOP1 inhibitors (“signature”), which include homologous recombination deficiency (HRD prominently represented by BRCA inactivation), overexpression of TOP1 and overexpression of a gene newly linked with response, SLFN11 (Schlafen 11), and could be used for patient selection and improving precision medicine. We will also report the burgeoning field of tumor-targeted delivery TOP1 inhibitors in clinical trials, which includes liposomal formulations (Onivyde), PEG conjugates (CRLX101; NKTR-102; PLX038, NK012), ADC (antibody drug conjugates: IMMU-132; IMMU-130; DS-8201a). These tumor-targeted TOP1 inhibitors aim to target tumors while sparing the bone marrow without having the dose-limiting toxicity of alternative payloads.
Methods
This section does not apply
Results
This section does not apply.
Conclusions
In conclusion, TOP1 inhibitors are targeted therapies that are being improved by introducing novel chemical inhibitors, novel tumor-targeted delivery and predictive biomarkers (TOP1, SLFN11, HRD).
24IN - Targeting the DDR – DNA PK inhibition
- Frank T. Zenke (Darmstadt, DE)
- Frank T. Zenke (Darmstadt, DE)
Abstract
Background
Deoxyribonucleic acid-dependent protein kinase (DNA-PK) plays a critical role in the repair of DNA double strand break (DSBs). DNA double stranded breaks are the most lethal type of DNA lesion, and cells have developed two distinct repair pathways to protect the cell genome from the deleterious effect of DSBs. While homologous recombination occurs mainly during S and G2 phase and requires a homologous DNA template, non-homologous end-joining, (NEJH) uses direct ligation of DNA ends without a homologous DNA template and can therefore take place anytime during the cell cycle.
DNA-PK is a key enzyme in NHEJ-mediated repair of DSBs and, therefore, represents an attractive pharmacological target. Selective inhibition of DNA-PK could synergistically enhance the activity of many commonly used DSB inducing treatment modalities, such as radiotherapy and certain chemotherapeutic agents.
The presentation will provide an overview of the biological role of DNA-PK in normal and cancer cells, available pre-clinical data that explore the effect of DNA-PK inhibition in vitro and in vivo, and early data from DNA-PK inhibitors currently in clinical development.
Legal entity responsible for the study
Merck
Funding
Has not received any funding
Disclosure
F.T. Zenke: Employee and stockholder of Merck KGaA.
25IN - DNA and immunotherapy: Synergies of combinations
- Richard Kennedy (Craigavon, GB)
- Richard Kennedy (Craigavon, GB)
Abstract
Background
In cancer the presence of T cell immune infiltration has been recognised as a prognostic factor, however the mechanisms underpinning this response are not clearly defined. Our group and others have identified a relationship between type I Interferon immune signalling and loss of DNA repair, particularly the Fanconi Anemia pathway, in several different types of cancer. We therefore investigated the mechanism activating this immune response in the context of abnormal DNA repair.
Methods
Preclinical isogenic cell line systems and human tumours were used to identify the relationship between loss of function of DNA repair genes and activation of immune signalling. A panel of Chemotherapeutic agents were studied for their effect on immune activation.
Results
IHC analysis demonstrated that both intra-tumoral and stromal CD8+ and CD4+ T cell infiltration were associated with DNA repair deficient breast tumors. The CXCL10 and CCL5 cytokines as well as the immune checkpoint target PD-L1 were shown to be significantly up-regulated in DNA repair deficient tumours and in tissue culture models when compared to DNA proficent tumours. Furthermore, conditioned media from DNA repair deficient cell lines stimulated inward migration of peripheral blood mononuclear cells, when compared to media from proficient cells, indicating the presence of active cytokines. We identified constitutive activation of the innate immune pathway STING/TBK1/IRF3 specifically in DNA repair deficient tumour cells when compared to proficient cells and found that binding of the DNA sensor cGAS to cytosolic DNA fragments was required for this immune response. In addition, we identified several chemotherapeutic agents that were able to activate the immune response in DNA repair proficient cell lines through DNA damage, the development of cytoplasmic DNA fragments and the consequent activation of the STING/TBK1/IRF3 immune pathway.
Conclusions
We have identified that the STING/TBK1/IRF3 immune pathway is constitutively activated by cytoplasmic DNA in DNA repair deficient cancers and may explain lymphocytic infiltration and the response to immune checkpoint based therapy. Some conventional chemotherapy agents such as doxorubicin are able to active this pathway in DNA repair proficient cancers and may represent a logical combination with immune checkpoint targeted drugs in clinical trials.
Legal entity responsible for the study
Queen\'s University of Belfast
Funding
McClay Foundation
Disclosure
R. Kennedy: I receive payment as the Global VP and Medical Director for Almac Diagnostics.