Ruth Riisnaes
A5066136399- Prostate Cancer Treatment and Research
- Cancer, Lipids, and Metabolism
- Cancer Genomics and Diagnostics
- PARP inhibition in cancer therapy
- Advanced Breast Cancer Therapies
- Hormonal and reproductive studies
- Immunotherapy and Immune Responses
- DNA Repair Mechanisms
- PI3K/AKT/mTOR signaling in cancer
- Radiopharmaceutical Chemistry and Applications
- Ovarian cancer diagnosis and treatment
- Cancer Immunotherapy and Biomarkers
- RNA Interference and Gene Delivery
- Colorectal Cancer Treatments and Studies
- Eicosanoids and Hypertension Pharmacology
- Cancer Research and Treatments
- Molecular Biology Techniques and Applications
- BRCA gene mutations in cancer
- Endoplasmic Reticulum Stress and Disease
- Cancer Cells and Metastasis
- Cholesterol and Lipid Metabolism
- Prostate Cancer Diagnosis and Treatment
- Monoclonal and Polyclonal Antibodies Research
- Mass Spectrometry Techniques and Applications
- Heat shock proteins research
Institute of Cancer Research
2016-2025
Royal Marsden NHS Foundation Trust
2013-2023
Royal Marsden Hospital
2011-2023
National Health Service
2011-2016
Memorial Sloan Kettering Cancer Center
2013
Cornell University
2013
Wellcome Sanger Institute
2011
Arqule (United States)
2011
Prostate cancer is a heterogeneous disease, but current treatments are not based on molecular stratification. We hypothesized that metastatic, castration-resistant prostate cancers with DNA-repair defects would respond to poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibition olaparib.
BackgroundMetastatic castration-resistant prostate cancer is enriched in DNA damage response (DDR) gene aberrations. The TOPARP-B trial aims to prospectively validate the association between DDR aberrations and olaparib metastatic cancer.MethodsIn this open-label, investigator-initiated, randomised phase 2 following a selection (or pick-the-winner) design, we recruited participants from 17 UK hospitals. Men aged 18 years or older with progressing previously treated one two taxane...
AKT signaling is frequently deregulated in human cancers. MK-2206 a potent, oral allosteric inhibitor of all isoforms with antitumor activity preclinical models. A phase I study was conducted to investigate its safety, maximum-tolerated dose (MTD), pharmacokinetics (PKs), pharmacodynamics (PDs), and preliminary efficacy.Patients advanced solid tumors received on alternate days. Paired tumor biopsies were mandated at the MTD for biomarker studies. PD studies incorporated hair follicle...
Abstract Hormone-driven expression of the ERG oncogene after fusion with TMPRSS2 occurs in 30% to 70% therapy-naive prostate cancers. Its relevance castration-resistant cancer (CRPC) remains controversial as is not expressed some TMPRSS2-ERG androgen-independent xenograft models. However, unlike these models, CRPC patients have an increasing prostate-specific antigen, indicating active androgen receptor signaling. Here, we collected blood every month from 89 (54 chemotherapy-naive and 35...
Abstract Biomarkers for more precise patient care are needed in metastatic prostate cancer. We have reported a phase II trial (TOPARP-A) of the PARP inhibitor olaparib cancer, demonstrating antitumor activity associating with homologous recombination DNA repair defects. now report targeted and whole-exome sequencing serial circulating cell-free (cfDNA) samples collected during this trial. Decreases cfDNA concentration independently associated outcome multivariable analyses (HR overall...
Liquid biopsies have demonstrated that the constitutively active androgen receptor splice variant-7 (AR-V7) associates with reduced response and overall survival from endocrine therapies in castration-resistant prostate cancer (CRPC). However, these studies provide little information pertaining to AR-V7 expression (PC) tissue.Following generation validation of a potentially novel antibody for IHC, protein was determined 358 primary samples 293 metastatic biopsies. Associations disease...
Abstract Purpose: PI3K–Akt–mTOR and androgen receptor (AR) signaling are commonly aberrantly activated in metastatic castration-resistant prostate cancer (mCRPC), with PTEN loss associating poor prognosis. We therefore conducted a phase Ib/II study of the combination ipatasertib, an Akt inhibitor, CYP17 inhibitor abiraterone patients mCRPC. Patients Methods: were randomized 1:1:1 to ipatasertib 400 mg, 200 or placebo, 1,000 mg orally. Coprimary efficacy endpoints radiographic...
Loss of the tumor suppressor phosphatase and tensin homolog (PTEN) occurs frequently in prostate cancers. Preclinical evidence suggests that activation PI3K/AKT signaling through loss PTEN can result resistance to hormonal treatment cancer.To explore antitumor activity abiraterone acetate (abiraterone) castration-resistant cancer (CRPC) patients with without protein expression.We retrospectively identified who had received hormone-sensitive (HSPC) and/or CRPC tissue available for...
Resistance to androgen receptor (AR) blockade in castration-resistant prostate cancer (CRPC) is associated with sustained AR signaling, including through alternative splicing of (AR-SV). Inhibitors transcriptional coactivators that regulate activity, the paralog histone acetyltransferase proteins p300 and CBP, are attractive therapeutic targets for lethal cancer. Herein, we validate targeting p300/CBP as a strategy describe CCS1477, novel small-molecule inhibitor conserved bromodomain. We...
PURPOSE Preclinical studies demonstrated that ATR inhibition can exploit synthetic lethality (eg, in cancer cells with impaired compensatory DNA damage responses through ATM loss) as monotherapy and combined DNA-damaging drugs such carboplatin. PATIENTS AND METHODS This phase I trial assessed the inhibitor M6620 (VX-970) (once or twice weekly) carboplatin (carboplatin on day 1 days 2 9 21-day cycles). Primary objectives were safety, tolerability, maximum tolerated dose; secondary included...
BACKGROUND. Understanding the integrated immunogenomic landscape of advanced prostate cancer (APC) could impact stratified treatment selection.
Abstract PARP inhibitors are approved for treating advanced prostate cancers (APC) with various defective DNA repair genes; however, further studies to clinically qualify predictive biomarkers warranted. Herein we analyzed TOPARP-B phase II clinical trial samples, evaluating whole-exome and low-pass whole-genome sequencing IHC IF assays ATM RAD51 foci (testing homologous recombination function). BRCA1/2 germline somatic pathogenic mutations associated similar benefit from olaparib; greater...
Abstract Inflammation is a hallmark of cancer 1 . In patients with cancer, peripheral blood myeloid expansion, indicated by high neutrophil-to-lymphocyte ratio, associates shorter survival and treatment resistance across malignancies therapeutic modalities 2–5 Whether inflammation drives progression prostate in humans remain unclear. Here we show that inhibition chemotaxis can reduce tumour-elicited reverse therapy subset metastatic castration-resistant (CRPC). We higher ratio reflects...
The hepatocyte growth factor/c-MET axis is implicated in tumor cell proliferation, survival, and angiogenesis. ARQ 197 an oral, selective, non-adenosine triphosphate competitive c-MET inhibitor. A phase I trial of was conducted to assess safety, tolerability, target inhibition, including intratumoral signaling, apoptosis, angiogenesis.Patients with solid tumors amenable pharmacokinetic pharmacodynamic studies using serial biopsies, dynamic contrast-enhanced magnetic resonance imaging...
Abstract Purpose: We evaluated whether next-generation sequencing (NGS) of circulating cell-free DNA (cfDNA) could be used for patient selection and as a tumor clone response biomarker in patients with advanced cancers participating early-phase clinical trials targeted drugs. Experimental Design: Plasma samples from known mutations who completed at least two courses investigational therapy were collected monthly, until disease progression. NGS was performed sequentially on the Ion Torrent...
Tumor genomic instability and selective treatment pressures result in clonal disease evolution; molecular stratification for molecularly targeted drug administration requires repeated access to tumor DNA. We hypothesized that circulating plasma DNA (cpDNA) advanced cancer patients is largely derived from tumor, has prognostic utility, can be utilized multiplex mutation sequencing when repeat biopsy not feasible. the Sequenom MassArray System OncoCarta panel somatic profiling. Matched...
Abstract Purpose: CHD1 deletions and SPOP mutations frequently cooccur in prostate cancer with lower frequencies reported castration-resistant (CRPC). We monitored expression during disease progression assessed the molecular clinical characteristics of CHD1-deleted/SPOP-mutated metastatic CRPC (mCRPC). Experimental Design: identified 89 patients mCRPC who had hormone-naive tumor samples available: These were analyzed for CHD1, PTEN, ERG by IHC. status was determined targeted next-generation...
Deletion of the chromatin remodeler chromodomain helicase DNA-binding protein 1 (CHD1) is a common genomic alteration found in human prostate cancers (PCas). CHD1 loss represents distinct PCa subtype characterized by SPOP mutation and higher instability. However, role development vivo its clinical utility remain unclear.To study management, we generated genetically engineered mouse model with prostate-specific deletion murine Chd1 as well isogenic wild-type homozygous deleted benign lines....
Abstract Preclinical studies have demonstrated synergy between PARP and PI3K/AKT pathway inhibitors in BRCA1 BRCA2 (BRCA1/2)–deficient BRCA1/2-proficient tumors. We conducted an investigator-initiated phase I trial utilizing a prospective intrapatient dose- escalation design to assess two schedules of capivasertib (AKT inhibitor) with olaparib (PARP 64 patients advanced solid Dose expansions enrolled germline BRCA1/2-mutant tumors, or BRCA1/2 wild-type cancers harboring somatic DNA damage...
Deleterious ATM alterations are found in metastatic prostate cancer (PC); PARP inhibition has antitumour activity against this subset, but only some loss PCs respond. To characterise ATM-deficient lethal PC and to study synthetic therapeutic strategies for subset. We studied advanced biopsies using validated immunohistochemical (IHC) next-generation sequencing (NGS) assays. In vitro cell line models modified CRISPR-Cas9 impair function were generated used drug-sensitivity functional assays,...
Abstract Purpose: Circulating tumor cells (CTCs) have clinical relevance, but their study has been limited by low frequency. Experimental Design: We evaluated liquid biopsies apheresis to increase CTC yield from patients suffering metastatic prostate cancer, allow precise gene copy-number calls, and disease heterogeneity. Results: Apheresis was well tolerated allowed the separation of large numbers CTCs; average 7.5 mL peripheral blood 167 CTCs, whereas per (mean volume: 59.5 mL) 12,546...
Activation of the PI3K/AKT/mTOR pathway through loss phosphatase and tensin homolog (PTEN) occurs in approximately 50% patients with metastatic castration-resistant prostate cancer (mCRPC). Recent evidence suggests that combined inhibition androgen receptor (AR) AKT may be beneficial mCRPC PTEN loss.
B7-H3 is a cell surface immunomodulatory glycoprotein overexpressed in prostate cancers (PCs). Understanding its longitudinal expression at emergence of castration resistance and association with tumour genomics are critical to the development patient selection for targeted therapies.To characterise same-patient hormone-sensitive (HSPC) castration-resistant (CRPC) PC biopsies, associating this genomics, evaluate antitumour activity an anti-B7-H3 antibody-drug conjugate (ADC) human CRPC vitro...