Urothelial Cancer

This study highlights the importance of MPTDN-related signatures in predicting GC prognosis and guiding therapeutic decisions.

Several FGFR inhibitors have been studied or are in development, and erdafitinib is the sole inhibitor to achieve regulatory approval...In this review, we describe known mechanisms of FGFR inhibitor resistance, including gatekeeper mutations, domain mutations, and the development of new mutations. In addition, we discuss management strategies, including ongoing clinical trials evaluating FGFR inhibitors, antibody-drug conjugates, and combination therapies with immune checkpoint inhibitors that may provide additional treatment options for localized and metastatic urothelial carcinoma.

P2, N=60, Recruiting, John Sfakianos | Not yet recruiting --> Recruiting

P1/2, N=5, Active, not recruiting, Case Comprehensive Cancer Center | Recruiting --> Active, not recruiting | N=15 --> 5

Today, novel agents called antibody drug conjugates (ADCs), including enfortumab vedotin (EV) and sacituzumab govitecan (SG), have been approved for la/mUC offering patients treatment options following or instead of traditional chemotherapy...In 2023, EV in combination with pembrolizumab almost doubled progression-free and overall survival versus platinum-based chemotherapy, which led to accelerated FDA approval as first-line treatment for all patients with la/mUC...Finally, a recent cancer agnostic accelerated approval for trastuzumab deruxtecan (T-DXd) in HER2-positive (IHC3+) solid tumors provides another active ADC option for biomarker-selected patients with treatment refractory la/mUC. Several new ADCs are being investigated in urothelial cancer (UC) clinical trials. This review summarizes the clinical studies and real-world data regarding the use of ADCs in UC.

Two enzymes involved in the heme synthesis pathway, coproporphyrinogen oxidase and ferrochelatase, exhibit a circadian rhythm. The fluorescence intensity started gradually increasing at 12 p.m., and the highest level was observed in patients who underwent surgery between 3 and 5 p.m. Our findings suggest that it may be possible to optimize the timing of the photodynamic diagnosis in photodynamic diagnosis-assisted transurethral resection of bladder cancer based on the circadian rhythm to improve tumor detection and treatment outcomes.

In summary, these data show that PLAP is expressed in a significant fraction of pT2-4 urothelial carcinomas, unrelated to cancer aggressiveness but associated with specific molecular features. Once anti-PLAP cancer drugs become effective, urothelial carcinoma is a candidate tumor entity for clinical evaluation.

P1, N=30, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Dec 2024 --> Dec 2025

P2, N=40, Recruiting, ImmunityBio, Inc. | Active, not recruiting --> Recruiting | N=147 --> 40

P1, N=100, Recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2024 --> Dec 2027 | Trial primary completion date: Dec 2024 --> Dec 2027

Kaplan Meier test identified high CD105-MVD as strong predictor of poor RFS in NMIBC patients. Association of CD105 expression and MVD with the clinicohistopathological features as well as poor survival outcomes potentially identify it as a preferred marker of clinical significance in a given cohort of UCB patients.Clinical significanceStrong association of CD105 at message level with the demographics of UCB patients identifies it as a marker of diagnosis in a given cohort of patients.Survival analysis examined CD105-MVD as an independent strong predictor of poor recurrence free survival in NMIBC patients.Present study provides clear evidence of increased vascular density, vascular sprouts proliferation and new blood vessel formation with disease aggressiveness indicating CD105 as a preferred marker of neoangiogenesis in the given cohort of patients.The study describes CD105-MVD as a biomarker of diagnosis and prognosis with the sensitivity of 91.67% and 93.33% in a given cohort of NMIBC and MIBC patients.

Our finding that Tacstd2/TACSTD2 is prevalent in cysts, but not normal tissue, suggests that it should be explored as a candidate for drug development in PKD. More immediately, our work suggests that PKD patients undergoing TACSTD2-directed treatment for breast and urothelial cancer should be monitored for kidney effects.

P=N/A, N=103, Recruiting, RenJi Hospital | Trial completion date: Dec 2024 --> Dec 2026 | Trial primary completion date: Dec 2023 --> Dec 2024

In a first-in-human phase 1-2a study (GDFATHER-1/2a trial, NCT04725474 ), patients with advanced cancers refractory to anti-PD-1 or anti-PD-L1 therapy (termed generally as anti-PD-1/PD-L1 refractoriness) were treated with the neutralizing anti-GDF-15 antibody visugromab (CTL-002) in combination with the anti-PD-1 antibody nivolumab. Increased levels of tumour infiltration, proliferation, interferon-γ-related signalling and granzyme B expression by cytotoxic T cells were observed in response to treatment. Neutralizing GDF-15 holds promise in overcoming resistance to immune checkpoint inhibition in cancer.

These findings suggest that the mGPS measured at the time of radiologic PD can identify patients with a better prognosis who may benefit from continued atezolizumab therapy, aiding in the selection for TBP in clinical practice.

P2, N=20, Recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Not yet recruiting --> Recruiting

In conclusion, our data demonstrate significant levels of CLDN3 expression in many different tumor entities and identify reduced CLDN3 expression as a potential prognostic marker in RCC.

Focal barbotage samples enable identification of gene mutations and other genetic aberrations that may add important prognostic information to histopathology and cytology. Refined prognostication of UTUC patients already at diagnosis can guide treatment decisions and follow-up programmes.

P2, N=0, Withdrawn, MedPacto, Inc. | N=48 --> 0 | Not yet recruiting --> Withdrawn

P=N/A, N=40, Active, not recruiting, University Teaching Hospital Hall in Tirol | Recruiting --> Active, not recruiting | Trial primary completion date: Aug 2022 --> May 2025

P=N/A, N=25, Completed, Leiden University Medical Center | Recruiting --> Completed | N=120 --> 25

These senescent UCs were not eliminated by the senolytic combination of Dasatinib and Quercetin...These findings illustrate the heterogeneity of cellular senescence in varied tissues, while also providing potential insights into the origin of urothelial cancer. We conclude that senescence of bladder uroepithelial cells plays a role in normal physiology, namely in their role as barrier cells, helping promote uroepithelial integrity and impermeability and maintaining the urine-blood barrier.

This study highlights the differential expression of BMAL-1, AURKA, and GSK-3β in association with arsenic exposure and their significant impact on clinical and pathological features of UC. Moreover, BMAL-1, AURKA, and GSK-3β emerge as potential prognostic markers for UC in regions with arsenic exposure.

While the full potential for MRD applications has yet to be realized, we are witnessing the emergence of novel techniques aimed at MRD detection and the rapid development of elegantly designed studies implementing iterative detection of MRD as means to provide biological rationale and tailor therapeutic options in GU tumors.

P1, N=130, Active, not recruiting, Celldex Therapeutics | Recruiting --> Active, not recruiting | Trial completion date: Feb 2026 --> May 2025 | Trial primary completion date: Dec 2024 --> May 2025

This study identified several cell subpopulations influencing NMIBC recurrence, which were heavily infiltrated in the TME of recurrent NMIBC. Additionally, the enrichment of estrogen in urothelial cancer cells from various sources suggested a role of sex hormones in NMIBC recurrence.

Owing to the evidence of invasion of the mass into the levator ani muscle, she underwent laparoscopic rectal resection plus combined resection of the tumor, perineum, and levator ani muscle in October. Currently, she is 3 months postoperatively without evidence of recurrence.

P2, N=163, Active, not recruiting, Janssen Research & Development, LLC | Recruiting --> Active, not recruiting

In summary, this study provides insights on YAP1 signaling as a driver for cancer stemness and an inducer of immunosuppressive TIME. Moreover, the therapeutic efficacy of YAP1 attenuation indicates that combined blockade of YAP1 and immune checkpoints may yield clinical value for treating UCB patients.

P2, N=45, Active, not recruiting, Sun Yat-sen University | Recruiting --> Active, not recruiting | Trial completion date: Sep 2023 --> Oct 2025 | Trial primary completion date: Sep 2022 --> Aug 2024

P2, N=32, Not yet recruiting, University of Michigan Rogel Cancer Center | Trial completion date: Jul 2027 --> Nov 2027 | Initiation date: Oct 2024 --> Feb 2025 | Trial primary completion date: Jul 2027 --> Nov 2027

These results suggest a potential protective role of HOOK3 amplification in BUC. Further research is needed to explore the underlying mechanisms and their therapeutic potential for reducing BUC-related mortality.

During follow-up sensitivities and specificities of most urinary markers are higher compared to cytology for the detection of recurrent bladder cancer. BTA stat®, UBC® Rapid Test, and uromonitor® appear useful in this setting.

Non-UC malignancies seem to have a lower N4 positivity rate than UC. N4 positivity in bladder cancer appears to vary according to stage and presence of HS. The predictive and prognostic role of N4 must be further characterized in larger and prospective studies.

CD73 could be used to predict the prognosis of patients with several cancers. The potential functional mechanism of CD73 involved in cancer progress may not only dependent on its immunomodulatory effects.

A heightened receptivity was noted toward particular chemotherapy drugs, encompassing gemcitabine, vincristine, paclitaxel, gefitinib, and sorafenib, within this high-risk group. Conversely, a superior reaction to cisplatin was distinctly evident among those marked by low MSC scores... The five-gene MSC prognostic model demonstrates substantial efficacy in prognosticating clinical outcomes and gauging responsiveness to chemotherapy and immunotherapy regimens. The genes ZNF165, MXRA7, CEMIP, ARL4C, and CERCAM are underscored as promising candidates warranting further exploration for anti-MSC therapeutic strategies, thereby offering novel insights for personalized treatment approaches in BC.

P=N/A, N=156, Active, not recruiting, University of California, San Francisco | Trial completion date: Jul 2025 --> Mar 2027 | Trial primary completion date: Jul 2025 --> Mar 2027

P1, N=890, Active, not recruiting, Daiichi Sankyo Co., Ltd. | Recruiting --> Active, not recruiting

P1, N=120, Not yet recruiting, SystImmune Inc.

P1/2, N=46, Active, not recruiting, H. Lee Moffitt Cancer Center and Research Institute | Trial completion date: Oct 2025 --> Apr 2027 | Trial primary completion date: Oct 2024 --> Apr 2026

P2, N=64, Recruiting, Northwestern University | Not yet recruiting --> Recruiting | Initiation date: May 2025 --> Nov 2024

Strong expression of EGFR in tumours with higher grade validates its prognostic role and can be utilized for targeted therapy with potentially lifesaving consequences in patients presenting with urothelial carcinoma.