Publications

TPS5100 Background: NEPC is an aggressive cancer with poor prognosis. No standard treatment approach for NEPC exists and it remains an unmet need. NEPC is usually treatment-emergent, characterized by histological transformation from adenocarcinoma to a high-grade neuroendocrine tumor (NET), and may develop in 15%–20% of patients (pts) treated with standard prostate adenocarcinoma therapies, including novel hormonal therapies. The inhibitory Notch ligand, Delta-like ligand 3 (DLL3), is highly expressed on the surface of cancer cells, including NEPC cells, making it an attractive and a promising therapeutic target. AMG 757 is an HLE BiTE immuno-oncology therapy designed to redirect cytotoxic T cells to tumor cells by binding DLL3 on cancer cells and CD3 on T cells, resulting in T cell activation and expansion and T cell-dependent killing of tumor cells. AMG 757 showed in vitro activity in DLL3-expressing NETs, including NEPC. Preliminary results of an on-going first-in-human study suggest AMG 757 is safe and effective in pts with small cell lung cancer (NCT03319940), which prompted its study in NEPC. Methods: NCT04702737 is an open-label, phase 1b study evaluating AMG 757 infusion in pts with metastatic de novo or treatment-emergent NEPC, consisting of dose exploration and then dose expansion. Key eligibility criteria include adults (≥18 y) with NEPC whose disease progressed/recurred after ≥1 treatment course including a platinum-based regimen for de novo NEPC or an androgen signaling inhibitor, measurable disease per modified RECIST 1.1 per Prostate Cancer Working Group 3 modifications, ECOG performance status ≤2, life expectancy > 3 mo, adequate organ function, and no untreated/symptomatic brain metastases. Primary objectives are to evaluate safety and tolerability and determine the maximum tolerated dose or recommended phase 2 dose of AMG 757. Secondary objectives are to evaluate antitumor activity (ie, objective response, duration of response, progression-free survival, overall response) and characterize pharmacokinetics. The starting dose for dose exploration will be based on the dose deemed safe and tolerable in the ongoing trial of AMG 757 in SCLC. The study is open to enrollment. Clinical trial information: NCT04702737.

<title>Abstract</title> Despite initial responses to hormone treatment, metastatic prostate cancer invariably evolves to a lethal state. To characterize the intra-patient relationships of metastases that evade treatment, we performed genome-wide copy number profiling and bespoke approaches targeting the androgen receptor (<italic>AR</italic>) on 142 metastatic regions from 10 organs harvested post-mortem from nine men who died from prostate cancer. We identified diverse and patient-unique alterations clustering around the <italic>AR</italic> in metastases from every patient with evidence of independent acquisition of related genomic changes within an individual and, in some patients, the co-existence of <italic>AR</italic>-neutral clones. Using the genomic boundaries of pan-autosome copy number change, we confirmed a common clone of origin across metastases and diagnostic biopsies; and identified in individual patients, clusters of metastases occupied by dominant clones with diverged autosomal copy number alterations and cluster-specific <italic>AR</italic> gene architectures. Copy number boundaries identified treatment-selected clones with distinct lethal trajectories.

1. Unitary inhibitory postsynaptic currents (uIPSCs) were recorded in synaptically coupled pairs of CA1 hippocampal interneurons and pyramidal neurons in rat brain slices by using dual patch-clamp techniques. Paired-pulse modulation of uIPSCs at individual GABAergic synapses was tested. 2. GABAergic synapses could be divided into two subgroups, high and low failure, depending on their failure rate. 3. The external Ca2+ levels modulate the failure rate of uIPSCs. In 0.51 mM Ca2+, low-failure pairs had a high-failure characteristic, whereas high-failure pairs had a low-failure characteristic in 8 mM Ca2+. The results suggest that uIPSC failures result from the Ca2+-dependent release mechanism rather than axon propagation failures. 4. Paired-pulse facilitation (PPF) occurred in high-failure pairs when the interspike interval was 20 ms. Paired-pulse depression (PPD) was not predominant in high-failure pairs. 5. Potency of uIPSCs, the average amplitude of non-failure events, was enhanced by PPF, suggesting that multiple synapses connect each pair. Differing numbers of activated synapses contributed to the variable amplitude of uIPSCs from a given pair. 6. PPD occurred in low-failure pairs at the tested range of interspike intervals (20-200 ms). The uIPSC2 after a large uIPSC1 was smaller than the uIPSC2 after a small uIPSC1, suggesting that PPD is use dependent and due to a decrease in the quantal content (m) after the first release. 7. In 8 mM Ca2+, PPD occurred in high-failure pairs and was larger in low-failure pairs, suggesting that the occurrence of PPF or PPD depends on the baseline release probability. 8. The GABAB receptor antagonist CGP 55845A (5 microM) decreased the baseline release probability of inhibitory synapses and attenuated PPD indirectly, rather than by blocking presynaptic GABAB autoreceptors.

ABSTRACT Integration of clinical pharmacogenomics (PGx) within routine cancer care is limited despite frequent use of medicines impacted by PGx, evidence for the benefits of PGx, and the availability of international PGx clinical guidelines. Our study objective was to develop survey tools to assess PGx knowledge, attitudes, practices, perceptions, and education needs among (a) doctors, nurses, and pharmacists involved in cancer care (healthcare professionals, HCPs) and (b) adults who have received cancer treatment or their carers (consumers), with the view to informing implementation strategies for PGx in solid and hematologic cancers. Survey tools were developed in a three‐phase (ph) mixed‐methods approach. Content was informed by systematic literature review findings and framed by determinants of behavior as informed by the Theoretical Domains Framework (ph‐1). Refinement occurred through four separate priority partnership meetings (ph‐2). Meetings focused on clinical PGx practices within select cancer streams, and consumers' knowledge, attitudes, and preferences for PGx testing. Content/face validity and health literacy (Flesch Kincaid Grade Level) assessments informed final refinements (ph‐3). Separate HCP and consumer survey tools were developed with six common sections: (1) introduction; (2) demographics; (3) experience; (4) knowledge, attitudes, practices and perceptions; (5) education; and (6) vignettes. Content and face validity were rated highly with acceptable health literacy assessments for questions within the consumer survey (median grade level 6; range 1–8). The developed survey tools will be used to generate evidence to inform local implementation strategies for PGx in cancer and promote broader integration of pharmacogenomics in routine clinical care.

&lt;p&gt;Supplementary Materials and methods&lt;/p&gt;

&lt;p&gt;Fig S1: Generation and characterisation of an androgen-dependent Hi-MYC epithelial line from 5-month Hi-MYC lateral prostate adenocarcinoma. Fig S2: CX-6258 does not inhibit Ribosomal RNA transcription. Fig S3: CX-6258 does not induce p53, but does induce low level p21 expression Fig S4: CX-5461 co-operates with Everolimus (RAD001) in vitro, but this does not suppress Hi-MYC tumorigenesis Fig S5: 5 month old Hi-MYC mouse prostate and body weight Fig S6: Influence of the androgen receptor on growth inhibition sensitivity&lt;/p&gt;

Peripheral T-cell lymphomas (PTCLs) are distinct pathological entities with clinical advancements lagging behind their B-cell lymphoma counterpart. Frequently aggressive in their clinical behaviour, clinicians are constantly challenged with low complete remission rates, early relapses and failure to achieve long-term responses despite aggressive first-line chemotherapy, resulting in poor overall survival in the majority of patients. There is currently no consensus regarding the optimal therapy for PTCL and treatment approaches are mainly derived from prospective phase II studies, registry data and retrospective studies. Despite its biological heterogeneity, a less than satisfactory “one-size-fits-all” approach has been adopted to date. Although its role remains controversial, for many years, haematopoietic stem cell transplantation has been adopted by clinicians with the aim of overcoming poor outcomes by consolidating responses. In this review, we aim to define the role of both autologous and allogeneic stem cell transplantation in PTCL in both frontline and salvage settings, especially in the context of recent advancements in this field.