P=N/A, N=17, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Apr 2024 --> Apr 2025 | Trial primary completion date: Apr 2024 --> Apr 2025

P1, N=36, Recruiting, Telix Pharmaceuticals (Innovations) Pty Limited | Phase classification: P1b --> P1

Molecular docking studies were performed to demonstrate the presence of numerous hydrogen bonds and hydrophobic interactions between the compounds and the active site of hCA. Absorption, distribution, metabolism, excretion (ADME) predictions showed that all of the compounds had good pharmacokinetic and physicochemical properties.

[177Lu]Lu-DPI-4452 demonstrated strong tumor growth inhibition in 2 xenograft mouse models. Thus, the 2 agents potentially provide a theranostic approach for selecting and treating patients with CAIX-expressing tumors such as ccRCC, CRC, and pancreatic ductal adenocarcinoma.

Mechanistic investigation using western blotting revealed compound 8q exerted the anti-migrative and anti-invasive effects probably through mitochondria-mediated PI3K/AKT pathway by targeting CAIX. In summary, coumarin-3-sulfonamide derivatives were developed as potential and effective CAIX inhibitors, which were worthy of further investigation.

This new H2MacropaSqOEt chelator was used to modify a monoclonal antibody, girentuximab (hG250), that binds to carbonic anhydrase IX, an enzyme that is overexpressed on the surface of cancers such as clear cell renal cell carcinoma...Evaluation of [225Ac]Ac(MacropaSq-hG250) in a mouse xenograft model, that overexpresses carbonic anhydrase IX, demonstrated a highly significant therapeutic response. It is likely that H2MacropaSqOEt could be used to modify other antibodies providing a readily adaptable platform for other actinium-225 based therapeutics.

Our study successfully applied computational strategies to discover three non-sulfonamide inhibitors of carbonic anhydrase IX (CA IX) that demonstrate inhibitory activity in vitro. These findings have significant implications for the development of CA IX inhibitors and anti-tumor drugs, contributing to their progress in the field.

[68Ga]Ga-DPI-4452, a first-in-class carbonic anhydrase IX-binding radiolabeled peptide, is the imaging agent of a theranostic pair with [177Lu]Lu-DPI-4452, developed for selecting and treating patients with carbonic anhydrase IX-expressing tumors...No clinically significant toxicity was observed. [68Ga]Ga-DPI-4452 showed exceptional tumor uptake in patients with clear cell renal cell carcinoma, with very high tumor-to-background ratios and no significant adverse events, suggesting potential diagnostic and patient selection applications.

The IC50 values of J16 for MDA-MB-231 and MCF-7 cells, under normoxic condition were 6.3 and 3.7 µM respectively, which are 1.9/3.3 and 15.8 times better than U-4-Nitro and SLC-0111 respectively...Expression of the other apoptosis markers Bcl-2, Bim, caspase 9 and caspase 3 substantiated the apoptosis mechanism. However, decreased transcription/expression of HIF1A/HIF-1α and hCA-IX/XII also implies the inhibition of the extracellular signal-regulated kinase pathway by J2 and J16.

P1/2, N=100, Active, not recruiting, M.D. Anderson Cancer Center | Suspended --> Active, not recruiting | Phase classification: P2 --> P1/2

TThese results propose that the MMH-1 compound could triggers apoptosis in MDA-MB-231 cells via the pH/MMP/ROS pathway through the inhibition of CA IX. This compound is thought to have high potential and promising anticancer properties in the treatment of aggressive tumors.

P2, N=100, Suspended, M.D. Anderson Cancer Center | Recruiting --> Suspended

P2, N=100, Recruiting, M.D. Anderson Cancer Center | Phase classification: P1b/2 --> P2

Many studies in multiple solid tumour models have demonstrated that targeting CAIX activity with the selective CAIX/XII inhibitor, SLC-0111, results in anti-tumour efficacy, particularly when used in combination with chemotherapy or immune checkpoint blockade, and has now advanced to the clinic...Importantly, the data from these models demonstrates that CAIX inhibition may sensitize tumour cells to cytotoxic drugs and evidence now points to ferroptosis, an iron-dependent form of regulated cell death (RCD) that results from accumulation of toxic levels of phospholipid peroxidation as a major mechanism involved in CAIX-mediated sensitization to cancer therapy. In this mini-review, we discuss recent advances demonstrating the mechanistic role CAIX plays in sensitizing cancer cells to ferroptosis.

The combination of nivolumab plus cabozantinib was recently approved for the first-line treatment of ccRCC based on the CheckMate 9ER phase 3 study demonstrating improved progression-free survival (PFS) & objective response rate (ORR) in comparison to sunitinib...To explore the effects of the treatment on inducing activated T cell infiltration, patients will undergo pre/post-treatment PET scan with [18F]F-AraG radiotracer as well as biopsies for single cell, spatial transcriptomics and proteomics studies. Clinical trial information: NCT05239533.

[68Ga]Ga-DPI-4452 provides exceptional images in patients with ccRCC without clinically significant toxicity. Very high SUVs and tumor-to-background ratios suggest potential for use in both diagnostics and patient selection for therapy. The tumor retention and rapid elimination support potential of [177Lu]Lu-DPI-4452 radioligand therapy.

These findings suggest that S100P could serve as a promising biomarker for immunosuppressive microenvironment, which may provide a novel therapeutic way for pancreatic cancer.

The presence of a 4-F-CH moiety, also found in SLC-0111, afforded an excellent selectivity towards the tumor-associated hypoxia-induced hCA isoform XII with an inhibition constant (K) of 4.5 nM. The 2-naphthyl derivative was the most potent inhibitor against hCA IX (K = 6.2 nM), 4-fold stronger than AAZ (K = 25 nM) with very good selectivity. Some compounds were chosen for antiproliferative activity testing against a panel of 3 human tumor cell lines, one compound showing anti-proliferative activity on glioblastoma, triple-negative breast cancer, and pancreatic carcinoma cell lines.

In a cohort of GC patients who received perioperative FLOT (i.e., Leucovorin, 5-Fluouracil, Docetaxel, and Oxaliplatin) or FOLFOX (i.e., Leucovorin, 5-Fluouracil, and Oxaliplatin), non-responder patients showed an increased expression of tumor CAIX compared to responder group. Moreover, GC cell lines induced to be resistant to 5-Fluouracil, Paclitaxel, Cisplatin, or the combination of 5-Fluorouracil, Oxaliplatin, and Docetaxel, overexpressed CAIX compared to the control...Notably, SLC0111 significantly improved the therapy response of both wild-type and resistant GC cells. Overall, these data suggest a correlation between CAIX and GC drug resistance highlighting the potential of SLC-0111 in re-sensitizing GC cells to pCT.

Promising candidates were assessed for VEGFR-2 inhibition and selectivity and further evaluated on breast cancer cell lines (MCF-7 and T-47D) and the non-tumorigenic (MCF-10A) cells. Molecular docking studies explored the binding modes of the sulfonamides against hCA IX/XII and VEGFR-2 kinase.

A host of new preclinical data and several clinical trials of antibodies and small molecule inhibitors are ongoing, which connected with the large number of new chemotypes/procedures discovered to be effective, may lead to a breakthrough in this therapeutic area. The scientific/patent literature has been searched for on PubMed, ScienceDirect, Espacenet and PatentGuru, from 2018 to 2023.

P1b, N=30, Recruiting, British Columbia Cancer Agency | Suspended --> Recruiting | Trial completion date: Dec 2024 --> Aug 2025 | Trial primary completion date: Jul 2024 --> Feb 2025

SLC-0111, a ureido benzenesulfonamide, is a selective human carbonic anhydrase (hCA) IX inhibitor in clinical trials for the treatment of hypoxic malignancies...Thereafter, Annexin V-FITC apoptosis detection, cell cycle, TUNEL, and qRT-PCR, colony formation, and wound healing assays were applied to gain mechanistic insights and to understand the behavior of colorectal cancer cells upon the treatment of compound 8g. Also, a molecular docking analysis was conducted to provide in silico insights into the reported hCA IX inhibitory activity and selectivity.

P1b/2, N=100, Recruiting, M.D. Anderson Cancer Center | Not yet recruiting --> Recruiting | Initiation date: May 2024 --> Jun 2023

Altogether, these findings suggest S4 as a novel ICD inducer in glioma and might have implications for S4-based immunotherapy. Video Abstract.

P1b/2, N=100, Not yet recruiting, M.D. Anderson Cancer Center | Initiation date: May 2023 --> May 2024

The model considers treatment with the small molecule CAIX inhibitor SLC-0111 in combination with ICIs...Concluding, we have developed a model that reproduces experimental findings and enables the investigation of combination therapies. Our model suggests that transient CAIX inhibition may induce tumor regression, given a sufficient immune infiltrate in the tumor, which can be boosted with ICIs.

No abstract available

No abstract available

Inhibition of CA IX by SLC-0111 reduced the expression levels of PDL-1, p-STAT3, and Glut-1, and reversed TE-ADSC-induced acidic TME in TNBC cells.ConclusionTaken together our results demonstrate the crucial role played by TE-ADSCs in promoting immune surveillance by inducing an acidic TME in TNBC. Furthermore, we highlight the possibility to sensitize tumor cells to ICIs by targeting CAIX using SLC-0111.

Importantly, CA IX inhibitors strongly reduced the growth and survival also of Bortezomib-resistant MM cells, and CA IX inhibitors combined with Bortezomib exerted an increased anti-myeloma activity compared to single treatments. Finally, both SLC-0111 and FC-531 significantly reduced the growth of MM tumor xenografts in NOD/SCID mice. ConclusionOur data suggest that CA IX inhibitors as single agents or in combination with proteasome inhibitors may represent a valid therapeutic approach for both naïve and proteosome inhibitor-refractory MM patients.

Additionally, newer modalities, such as contrast-enhanced ultrasound, dual energy computed tomography, and molecular imaging, will be discussed in conjunction with emerging radiomics and artificial intelligence techniques. Current diagnostic algorithms combined with newer approaches may be an effective way to overcome existing limitations in renal mass and RCC characterization.

P1b, N=36, Recruiting, Telix International Pty Ltd | Not yet recruiting --> Recruiting

P1b, N=36, Not yet recruiting, Telix International Pty Ltd

P=N/A, N=17, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Apr 2023 --> Apr 2024 | Trial primary completion date: Apr 2023 --> Apr 2024

Coprimary objectives were to evaluate both the sensitivity and specificity of TLX250-CDx PET/CT imaging in detecting ccRCC in patients with IDRM, using histology as standard of truth. 89 Zr-DFO-girentuximab PET/CT is well tolerated and can accurately and noninvasively identify and characterize IDRMs, showing promising utility for guiding surgical and treatment decisions.

In addition, combined CAIX/CAXII knockdown and more effective treatment with SLC-0111 reduced clonogenic survival of CMS3 modelling single cells. In conclusion, the preclinical data support the clinical approach of targeted CAIX/CAXII inhibition by showing linkage of expression with response and suggest that patients with CMS3-classified tumors would most benefit from such treatment.

P1, N=50, Not yet recruiting, Mabpro, a.s. | Trial completion date: Jan 2026 --> Jan 2027 | Initiation date: Jan 2023 --> Jan 2024 | Trial primary completion date: Jan 2025 --> Jan 2026

In addition, both 4d and 4j showed up to 50-fold cancer cell selectivity compared to the non-cancerous HEK293T cells. Accordingly, this study presents 4d and 4j being new, synthetically accessible, simplistically designed derivatives as potential candidates to be further developed as anticancer therapeutics.

Twelve compounds were identified to be more potent compared with acetazolamide (AAZ) control to inhibit CA IX while one was also more potent than AAZ to inhibit CA XII. Compound 18f (Ki's = 955 nM, 515 nM, 21 nM and 5 nM for CA's I, II, IX, and XII, respectively) is highlighted as a novel CA IX and XII inhibitor for further development.

P2, N=12, Recruiting, Institut Cancerologie de l'Ouest | Trial completion date: Dec 2022 --> Jun 2024 | Trial primary completion date: Dec 2022 --> Mar 2024