Resource Type: Posters

Platinum-based therapy selects for an angiogenic enriched tumor micro-environment in High Grade Serous Ovarian Cancer

Background:

  1. Angiogenesis is a key pathological feature of epithelial ovarian cancer (EOC) and anti-angiogenics have dominated the field of drug development in EOC
  2. There are no clinically approved predictive biomarker to preselect the subgroup of high grade serous ovarian cancer (HGSOC) that will derive benefit from anti-angiogenic therapy
  3. Relapse post platinum-based therapy is associated with a beneficial response to anti-angiogenics
  4. Innate and acquired platinum resistance is characterized by upregulation of VEGFa and receptor tyrosine kinase expression that trigger an enriched angiogenic tumor micro-environment
  5. In-vitro and in-vivo angiogenesis assays demonstrate that platinum resistant cell lines are sensitive to Cediranib and Nintedanib

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Platinum therapy resistance is associated with an enrichment of tumor angiogenesis in epithelial ovarian cancer

  • The clinical and pre-clinical data discussed has potentially significant clinical implications in the management of treatment-relapsed HGSOC.
  • Platinum-resistance in relapsed HGSOC is an indicator for response to antiangiogenic agents.
  • The novel identification of chemotherapy-mediated selection for an angiogenic phenotype in EOC, through upregulation of the PDGFR-VEGF-A signaling pathway.
  • Targeted inhibition of PDGFR (using TKI or siRNA knockdown) reverses platinum therapy resistance in EOC.
  • This clinical and pre-clinical data supports the use of anti-angiogenic agents in the first and second line setting in patients with innate and acquired resistance to platinum therapy, respectively.

Identification of a high-risk subgroup in primary prostate cancers presenting with targetable immune biology

Integrative clustering of multi-omics data revealed 2 subgroups of patients with metastatic-like biology that have distinct biology. 17% of the patients show greater genomic instability and present with targetable immune biology –that can be identified with the combination of the DDRD and PCM assays. This subgroup can be reproduced with the expression of 8q genes alone. The group is also identified in an independent data set and represents 14% of the n=321 cohort. The Metastatic-like DDRD group is shown to be at increased risk of biochemical recurrence & metastatic disease. It may represent a viable target population for immune checkpoint and DNA damaging treatment.

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DNA Damage Response Deficiency (DDRD) in Breast Cancer is associated with a STING-dependent Innate Immune Response

Key Findings:

  • DNA damage response deficient human breast cancers are associated with CD8+ and CD4+ lymphocytic infiltration.
  • The epithelial component of DDRD tumors releases chemokines that can account for lymphocytic infiltration.
  • Chemokine release is dependent on activation of the cGAS-STING-IRF3 pathway which is constitutively activated in DNA repair deficient cells, or by exogenous DNA damaging agents.
  • Activation of the cGAS-STING-IRF3 pathway is cell cycle specific and is associated with an accumulation of cytosolic DNA in the S-phase of the cell cycle.
  • Activation of the cGAS-STING-IRF3 pathway is associated with expression of the immune-checkpointinggene PD-L1 which may prevent immune-mediated tumorcell death.
  • This may provide a therapeutic rationale for immune-checkpoint targeted therapies in the context of DNA damage response deficiency in cancer.

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The development and utilization of a novel DNA microarray platform for biomarker and target identification in advanced prostate cancer

Prostate cancer is the second leading cause of cancer-related deaths in men; specifically one in six men are diagnosed with prostate cancer in their lifetime.

The use of serum prostate-specific antigen (PSA) levels has been recognized as a huge step forward in the diagnosis and treatment of prostate cancer, however since its implementation as a biomarker it has become apparent that the numbers of deaths from prostate cancer has only decreased slightly. Therefore the identification of new biomarkers and treatments for highly invasive/metastatic prostate cancers is of a high priority.

Almac sought to identify new biomarkers and drug targets by performing DNA microarray analysis of high Gleason score prostate tumor samples and normal prostate tissue samples. To further these goals we developed a specific array platform, this array was based upon extensive sequencing of prostate tumor samples and contains approximately 90,000 probesets, many of which are specific to prostate cancer.

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DNA Damage Response Deficiency Assay predicts response to treatment in ovarian cancer

Ovarian cancer is the leading cause of death from gynecological malignancies. The standard first line therapy is a combination of carboplatin and paclitaxel and has a response rate of 70%-80%, although the majority relapse. Almac have previously developed a 44 transcript DNA damage response deficiency (DDRD) assay which indicates loss of the FA/BRCA pathway and predicts response to DNA damaging agents.

In this study we have investigated the utility of the DDRD assay predicting response to platinum based therapy in ovarian cancer.

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Development of Expression Based Biomarkers in NSCLC: A Study of Intratumor Heterogeneity Using FFPE Tissue

There is considerable interest in the use of gene expression data to generate predictive and prognostic biomarkers from archived non-small cell lung cancer (NSCLC) tissue (Potti et al., 2006). In early stage disease, up to twenty FFPE blocks are available from each patient. Since NSCLC tumors exhibit histological diversity, it is possible that areas of individual tumors represented by different FFPE blocks will exhibit distinct molecular profiles (Sakurada et al., 2008). This intratumoral  heterogeneity represents a potential problem for the development of biomarkers from NSCLC tissue. This study examines gene expression data in multiple FFPE blocks taken from individual patients. Variations in gene expression are analyzed between:

  • FFPE blocks of individual patients
  • Whole FFPE sections and macrodissected tumor tissue
  • Individual patients
  • Disease histologies (squamous and adenocarcinoma

The study also evaluates the impact of these variations on powering clinical biomarker discovery studies.

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Identification of a novel breast cancer molecular subgroup associated with a deficiency in DNA-damage response

The loss of function of several DNA-damage response (DDR) genes has been reported in breast cancer. A dysfunction in DDR is exploited by DNA-damaging as well as novel targeted therapeutics such as PARP-1 inhibitors. Identification of those patients with DDR dysfunction could inform the selection of effective chemotherapeutic agents in the clinic. Almacreport the identification of a novel molecular subgroup in breast cancer related to DDR deficiency (DDRD) that can be identified by a 44 gene signature (DDRD signature). The DDRD signature is a significant predictor of BRCA and Fanconi anemia (FA) mutational status as well as an independent predictor of response to neoadjuvant anthracycline-based chemotherapy.

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