Clinical Cancer Research

BackgroundPoly (ADP-ribose) polymerase inhibitors (PARPi) are effective in patients with germline BRCA 1/2 and PALB2 mutations but have been largely ineffective as monotherapy in others. PARP interacts with, and is recruited to, DNA damage sites along with epigenetic factors, such as DNA methyltransferase 1 (DNMT1). In addition to increasing PARP-trapping, inhibitors of DNMT modulate ROS-cAMP/PKA signaling and induce a pathogen mimicry, inflammasome signaling response and a BRCAness phenotype t...

BackgroundCancers that do not respond to immunotherapy typically harbor a non-T cell-inflamed tumor microenvironment (TME), characterized by the absence of type I/II interferon (IFN) signaling and CD8+ T cell infiltration. We previously reported IDH1 somatic mutations were enriched in non-T cell-inflamed tumors across tumor types. Consistent with this, mutant IDH1 (mIDH1) has been demonstrated to drive immune exclusion through metabolic reprogramming of the TME, and IDH inhibition enhanced anti-...

IntroductionCombining antibody-drug conjugates (ADCs) with radioimmunotherapy is a feasible and highly promising approach for treating HER2-positive patients, offering a potential paradigm for pan-cancer therapy. ADCs have demonstrated significant efficacy in cancers expressing human epidermal growth factor receptor 2 (HER2), independent of the tumors tissue of origin. Preclinical studies suggest that ADCs not only induce immunogenic cell death but also selectively enhance tumor radiosensitivity...

PurposeAPX3330 is an oral agent targeting the redox signaling activity of Ape1/Ref-1 (Ref-1), a key regulator of transcription factors involved in inflammation and tumorigenesis. APX3330 selectively inhibits Ref-1s redox function without affecting its DNA repair role. This Phase 1, multicenter, open-label, dose-escalation study in advanced solid tumor was aimed at determining the recommended Phase 2 dose (RP2D) while assessing safety, pharmacokinetics, and biomarker evidence of target engagement...

BackgroundWe present the first clinical proof of concept using click chemistry to selectively capture drugs at tumors. SQ3370 combines a clickable pre-targeting agent (intratumorally injected biopolymer, SQL70) and a chemically-attenuated doxorubicin (Dox) protodrug (SQP33) that is activated upon clicking with the biopolymer at the tumor to rapidly release high local concentrations of native doxorubicin. MethodsThis was a Phase 1/2a open-label study in patients with advanced solid tumors (NCT04...

The development of DNA damage response (DDR)-directed therapies is a major area of clinical investigation, yet to date Poly (ADP-ribose) polymerase (PARP) inhibitors remain the only approved therapy in this space. Major challenges to DDR-targeted therapies in the post-PARPi era are the context dependency of DDR alterations and the presence of pre-existing resistance in this heavily pre-treated population. To that end, we used a contemporary platform to analyze pre-treatment circulating tumor DNA...

Immune-checkpoint blockade (ICB) has shown significant efficacy across various tumor types. However, tumors with low intraepithelial T-cell infiltration, often referred to as "cold" tumors, are expected to yield poor responsiveness to ICB. We investigated the potential of low-dose radiotherapy (LDRT) to enhance ICB responses in 25 patients with multimetastatic immune-excluded solid tumors through a multi-cohort phase I clinical trial (RACIN). Primary endpoint was to determine the safety and tole...

Immune checkpoint blockade impedes the negative regulatory signals for T-cell response and permits more effective immune detection and eradication of cancer cells. This single-arm phase II clinical trial (ACTRN12616001019493) within the Molecular Screening and Therapeutics (MoST) program evaluates the clinical activity and safety of combination immunotherapy with durvalumab and tremelimumab in patients with advanced cancers, prioritsing rare cancers (<6 per 100,000 annual incidence) and patients...

PurposeThis study aimed to stratify patients with locally advanced rectal cancer (LARC) based on their response to neoadjuvant chemoradiation therapy (nCRT) using DNA damage response (DDR)-related proteins measured in peripheral blood monocytes (PBMCs). We optimized and validated an innovative assay to quantify these proteins, providing a predictive framework for nCRT response. Experimental DesignWe used PBMCs collected from LARC patients either before or after standard course of [~]5.5 weeks o...

PurposeTreatment response assessment for patients with advanced solid tumors is complex and existing methods of assessment require greater precision for early disease assessment. Current guidelines rely on imaging, which has limitations such as the long time required before treatment effectiveness can be determined. Serial changes in whole-genome (WG) circulating tumor DNA (ctDNA) were used to detect disease progression early in the treatment course. Methods97 patients with advanced cancer were...

Tumor-associated macrophages (TAM) are critical determinant of resistance to programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) blockade. This phase I study (MEDIPLEX, NCT02777710) investigated the safety and efficacy of pexidartinib, a CSF-1R-directed tyrosine kinase inhibitor (TKI), and durvalumab (anti-PD-L1) in patients with advanced colorectal (CRC) and pancreatic (PDAC) carcinoma with the aim to enhance responses to PD-L1 blockade by eliminating CSF-1-dependent suppressive TAM. No u...

BackgroundCancer immunotherapy often triggers immune-related adverse events (irAEs). Analysis of irAEs in large checkpoint inhibitor (CPI) trials has enhanced their management and demonstrated their prognostic value for treatment outcome. However, data on irAEs in non-standard cancer immunotherapies (CITs) are limited, and systematic exploration is lacking. Identifying predictive biomarkers for irAEs in these therapies is still emerging and essential for improving patient care. MethodsWe establ...

PurposeTranscription-replication conflicts (TRCs) are a major source of endogenous replication stress in cancer. We previously discovered that pancreatic ductal adenocarcinoma (PDAC) demonstrates uniquely high levels of TRCs compared to other common solid tumors. Here, we characterize the mechanism of action, oncogene-dependency, PDAC subtype-specificity, and preclinical activity of a TRC-targeting small molecule - AOH1996 - in a spectrum of PDAC models. We also provide first clinical evidence o...

Belantamab mafodotin, an antibody-drug conjugate targeting B-cell maturation antigen, has demonstrated significant clinical efficacy in combination therapies for relapsed/refractory multiple myeloma. Belantamab mafodotin exerts therapeutic effects through cytotoxicity of its payload, monomethyl auristatin F, and through mediation of antibody-induced cell death. Long-term clinical responses were observed with monotherapy treatment, despite dose holds, suggesting adaptive immune system involvement...

PurposeWhile circulating tumor DNA (ctDNA) is a promising biomarker for minimal residual disease (MRD) detection in head and neck squamous cell carcinoma (HNSCC), more sensitive assays are needed for accurate MRD detection at clinically-relevant timepoints. Ultrasensitive MRD detection immediately after surgery could guide adjuvant therapy decisions, but early ctDNA dynamics are poorly understood. Experimental DesignWe applied MAESTRO, a whole-genome, tumor-informed, mutation-enrichment sequenc...

BackgroundNUC-3373 is a novel thymidylate synthase (TS) inhibitor designed to directly deliver the active anti-cancer metabolite fluorodeoxyuridine-monophosphate (FUDR-MP or FdUMP) intracellularly. In addition to being a potent TS inhibitor, NUC-3373 has also been shown to cause DNA damage and promote the release of damage-associated molecular patterns. These diverse mechanisms position NUC-3373 as a potentially effective combination partner for several other anti-cancer agents. MethodsNuTide:3...

BackgroundNeoadjuvant chemotherapy (NAC) is the standard of care for locally advanced breast cancer. However, the disconnect between efficacy in randomized trials and effectiveness in real-world practice--attributable to real-world treatment delays and adherence barriers--remains underexplored for early-stage (cT1-cT3) operable disease. MethodsWe applied the Target Trial Emulation (TTE) framework to a propensity-score matched cohort from the SEER database. To mitigate immortal time bias and sta...

Scheduling of oncolytic virus (OV) therapy has never been correlated with immunological /clinical response. In hepatocellular carcinoma (HCC) patients, where background liver is frequently chronically injured, repeated dosing may have deleterious implications, resulting in off-target immune-mediated damage, thereby tipping the balance between favourable clinical response and hepatotoxicity. Elucidation of the optimum dosing regime is paramount to ensure therapy, whilst limiting damage to backgro...

Many studies have reported biomarkers predictive of response to immune checkpoint inhibitors (ICI) based on retrospective analyses. However, few clinical trials have tested their value prospectively. The DUTRENEO trial (EudraCT: 2017-002246-6) investigated whether an 18-gene Tumour Inflammation Signature (TIS) that can robustly identify patients who respond to ICI in multiple tumour types could stratify patients with localized muscle-invasive bladder cancer (MIBC) to receive neoadjuvant ICI (dur...

BackgroundPreclinical studies support targeting PI3K/AKT/mTOR signalling in platinum-resistant ovarian cancer (PROC). A phase I study of the dual mTORC1/mTORC2 inhibitor vistusertib with weekly paclitaxel (wP) showed activity. We report the results of Arm 1 of OCTOPUS, the first randomised trial of weekly paclitaxel and dual mTORC1/2 inhibition in ovarian cancer. MethodsPatients with platinum-resistant or refractory high grade serous carcinoma were randomised (1:1) to wP (80mg/m2 D1,8,15 of 28 ...