Woomera Therapeutics

405 Background: While standard mpMRI has shown benefit in increasing detection of clinically significant prostate cancer, it is limited in its ability to detect small lesions, low Gleason scores, and certain tumor architectures. Proteomics may supplement imaging and enhance prediction of clinical outcomes. We investigated associations between MRI-mapped tumors and protein levels obtained from radical prostatectomy (RP) specimens and correlated them to adverse pathology features. Methods: This was an interim analysis of a planned cohort of 124 subjects. Patients underwent routine preoperative mpMRI and whole-mount histopathology after RP, with proteomic analysis performed on tissue from MRI-mapped tumors. A panel previously shown to improve prediction of distant metastasis in RP patients included five proteins: TGFβ-1, SPARC, FOLH1 (PSMA), CAMKK2, and tumor PSA. Protein concentrations were log transformed. Logistic regression assessed protein associations with adverse pathologic features, including extracapsular extension (ECE), seminal vesicle invasion (SVI), lymph node invasion (LNI), Gleason score ≥8, and a composite of these findings. Multivariate analyses were adjusted by patient age, PSA, Gleason Grade Group, and T stage at diagnosis. Results: 61 patients had proteomic data; mean age at diagnosis was 64 years and mean PSA at diagnosis 10 ng/dL. ECE was present in 67%, SVI 20%, LNI 21%, and Gleason score ≥8 26%; 72% had at least one adverse pathologic feature. On initial multivariate analysis of proteins alone, TGFβ-1 significantly correlated with LNI (odds ratio [OR] 24.4 [95% confidence interval (CI) 3.7-160.2], p = 0.0009) and composite adverse pathology (OR 3.1 [95% CI 1.0-9.3], p = 0.05). Even after including clinical characteristics in the model, TGFβ-1 still significantly correlated with LNI (Table). None of the other proteins significantly correlated to these markers of adverse pathology. Conclusions: In this study assessing protein associations with MRI-identified prostate tumors, TGFβ-1 was strongly predictive for LNI. TGFβ signaling has been associated with both prostate cancer suppression and promotion depending on context. Further investigation will assess if the combination of proteins in the panel is more predictive of adverse pathology. Multivariate logistic regression analyzing association between proteins and lymph node invasion. Protein Odds ratio (95% CI) p-value TGFβ-1 235.0 (4.5-N/A) 0.007* SPARC 1.4 (0.3-7.3) 0.7 FOLH1 0.8 (0.3-2.4) 0.7 CAMKK2 2.0 (0.7-5.8) 0.2 PSA 2.0 (0.7-5.6) 0.2 Protein concentrations were log transformed and models included patient age, PSA, Gleason Grade Group, and clinical T-stage at diagnosis.

Preclinical human inflammatory bowel disease (IBD) mechanisms is one of 5 focus areas of the Challenges in IBD Research 2024 document, which also includes environmental triggers, novel technologies, precision medicine, and pragmatic clinical research. Herein, we provide a comprehensive overview of current gaps in inflammatory bowel diseases research that relate to preclinical research and deliver actionable approaches to address them with a focus on how these gaps can lead to advancements in IBD interception, remission, and restoration. The document is the result of multidisciplinary input from scientists, clinicians, patients, and funders and represents a valuable resource for patient-centric research prioritization. This preclinical human IBD mechanisms section identifies major research gaps whose investigation will elucidate pathways and mechanisms that can be targeted to address unmet medical needs in IBD. Research gaps were identified in the following areas: genetics, risk alleles, and epigenetics; the microbiome; cell states and interactions; barrier function; IBD complications (specifically fibrosis and stricturing); and extraintestinal manifestations. To address these gaps, we share specific opportunities for investigation for basic and translational scientists and identify priority actions.

TPS3171 Background: The signal transducer and activator of transcription 3 (STAT3) protein is activated by cytokines and growth factors resulting in tumor growth and promotion and hindering antitumor immunity. Approximately 70% of human cancers including both hematological malignancies and solid tumors exhibit increased levels of phosphorylated STAT3 (pSTAT3). There is evidence of constitutive activation of STAT3 through genetic mutations or aberrant cellular signaling pathways in tumors such as large granular lymphocytic leukemia (LGL-L), peripheral T-cell lymphoma (PTCL), and cutaneous T-cell lymphomas (CTCL). Hyperactivation of STAT3 has been reported in a variety of solid tumors. In several of these cancers, the levels of pSTAT3 and/or activated STAT3 have been shown to correlate with poor clinical prognosis. As with other transcription factors, selective inhibition of STAT3 has been proven to be difficult with conventional therapeutic approaches. KT-333 is a potent highly selective, heterobifunctional small molecule degrader of STAT3. In preclinical studies, durable tumor regressions were seen with weekly KT-333 administration in STAT3-dependent T cell lymphomas, and antitumor activity was seen in solid tumors in combination with anti-PD1 (ASH 2021, SITC 2021). Methods: KT-333 is being evaluated in an open-label, dose escalation (Phase 1a, n = 40) study in patients with lymphomas relapsed or refractory (R/R) to at least two prior systemic treatments or for whom standard therapies are unavailable. Dose escalation will be conducted by accelerated titration followed by a 3+3 design in ascending doses of intravenous KT-333 administered once weekly in 28-day cycles to evaluate safety and define the maximum tolerated dose (MTD)/recommended Phase 2 dose (RP2D) (primary endpoint). Secondary endpoints include pharmacokinetics (PK) in plasma and urine and preliminary pharmacodynamic effects (PD) of KT-333 using blood (peripheral blood mononuclear cells [PBMCs], plasma/serum) and tumor tissue. After confirming the MTD/RP2D in patients with lymphoma, patients with advanced solid tumors will be enrolled in a separate Phase 1a cohort at the MTD/RP2D. In Phase 1b (n = 80), patients with PTCL, CTCL, LGL-L (T-cell LGL-L or chronic lymphoproliferative disorder of natural killer-cells), or solid tumors R/R to at least one prior systemic standard of care treatment or for whom standard therapies are not available, will be enrolled in separate 20 patient cohorts. This will further characterize safety, PK, PD and evaluate the clinical activity of KT-333. Treatment with KT-333 will continue until disease progression, unacceptable toxicity, or patient refusal. KT333-TL-101 began enrolling in January 2022. Clinical trial information: NCT05225584.