SLC34A2 expression

P3, N=20, Terminated, Mersana Therapeutics | N=350 --> 20 | Trial completion date: Mar 2025 --> Sep 2023 | Active, not recruiting --> Terminated | Trial primary completion date: Sep 2024 --> Sep 2023; Study Terminated by Sponsor

P3, N=350, Active, not recruiting, Mersana Therapeutics | Recruiting --> Active, not recruiting

Patients who received bevacizumab in combination with their most recent platinum containing regimen are excluded...NCT05329545. Clinical trial information: NCT05329545.

Background: Biomarker driven therapies are increasingly being used for gynecologic cancers, with mirvetuximab soravtansine, a Folate Receptor alpha (FRa) targeting antibody drug conjugate (ADC) being a recent FDA approved agent for patients with FRa positive PROC... Based on this analysis of a limited sample size, there does not appear to be an association between FRa and NaPi2b expression, with the majority of NaPi2b positive samples not being FRa positive. Additionally, general NaPi2b prevalence and the correlation of expression between RNA and IHC suggest that NaPi2b may be a rational biomarker to integrate in RNA tumor panel testing. This research underscores the importance of early, comprehensive testing of all relevant biomarkers to guide therapy selection, and suggests that additional research is needed to evaluate the potential association between FRa and NaPi2b expression via IHC.

P1b/2, N=444, Recruiting, Mersana Therapeutics | Trial completion date: Dec 2023 --> Dec 2024

UpRi is being evaluated in clinical trials, requiring either fresh or archival tissue for NaPi2b expression assessment. The high expression concordance rate seen suggests that NaPi2b remains consistent throughout chemotherapy treatment, supporting use of archival tissue for analysis.

P3, N=350, Recruiting, Mersana Therapeutics | Not yet recruiting --> Recruiting

Finally, we show that XPR1 requires the novel partner protein KIDINS220 for proper cellular localization and activity, and that disruption of this protein complex results in acidic "vacuolar" structures preceding cell death. These data point to the XPR1-KIDINS220 complex and phosphate dysregulation as a therapeutic vulnerability in ovarian cancer.

P3, N=350, Not yet recruiting, Mersana Therapeutics

High NaPi2b expression was noted in a significant subset of adenocarcinoma cases, and in particular amongst those who were TTF1+, or exhibited EGFR or KRAS mutations. This agrees with earlier reports and highlights the significance that NaPi2b may have a role as a possible target for delivery of cytotoxic agents via antibody-drug conjugate models for some patients with lung adenocarcinoma.

It was found that the life expectancy of breast and thymus cancer patients with an SLC34A2 mutation is lower, and it was revealed that SLC34A2 overexpression reduced the life span of patients with brain, ovarian, and pancreatic tumors. Thereby, for these types of oncological diseases, the mutational profile of SLC34A2 can be a potential prognostic marker for breast and thymus cancers, and the upregulation of SLC34A2 can be a potential prognostic marker for brain, ovarian, and pancreatic cancers.

TMPRSS3 overexpression in SLC34A2-deficient cells antagonized siSLC34A2-mediated cell cycle inhibition by promoting cyclin E, cyclin A protein expression. Based on these results, our study suggests that SLC34A2 promotes cancer proliferation and cell cycle progression by targeting TMPRSS3 in colorectal cancer cells.

The NaPi2b (67) assay system demonstrates a broad range of reproducible staining in OC. Current studies indicate that a ≥75% TPS cut-off could be used in a clinical setting for patient selection and identifies a similar population to the previously used H-score. This proposed CDx assay is currently being used in the UPLIFT Study Cohort of UpRi in OC (NCT03319628).

The 2 patients achieving CR had previously been treated with bevacizumab and PARPi (Richardson et al, ASCO 2021, TPS5607). Patients will be enrolled globally. ( NCT03319628 ).

P1b/2, N=444, Recruiting, Mersana Therapeutics | Trial completion date: Dec 2022 --> Dec 2023 | Trial primary completion date: Jul 2022 --> Apr 2023

The sodium-dependent phosphate transporter NaPi2b encoded by SLC34A2 gene is expressed in 80-90% of epithelial ovarian cancers and used as a target for therapeutic antibodies XMT-1536, and XMT-1592, which are derived from MX35 antibodies and used in clinical trials for the treatment of ovarian and lung cancers. In this work, we demonstrated that the expression of the human NaPi2b (hNaPi2b) transporter is downregulated in the tumors of patients receiving neoadjuvant therapy and during the development of disease. The data suggest that the level of expression of the SLC34A2 gene can serve as a potential marker for the monitoring and predicting responses to neoadjuvant and targeted therapy in patients with ovarian cancer.

Furthermore, this effect of SLC4A4 may be through the activation of JNK/P38 MAPK signaling pathway. Future in vivo and in vitro gain- or loss-of-function experiments are needed to verify these findings and further elucidate the deeper molecular mechanisms.

High SLC34A2 IHC expression correlated with adverse clinicopathological prognostic parameters. Furthermore, SLC34A2 was identified as an independent factor for DFS that could serve to improve risk stratification of PTC patients for better management.

P1/2, N=422, Ongoing, Mersana Therapeutics, Inc.

Observation of preliminary antitumor activity was reported in the ovarian cancer expansion cohort, including in patients previously treated with bevacizumab and PARPi (Tolcher et al, ASCO 2019; Richardson et al, ASCO 2019; Hamilton et al, ESMO 2020) . This study is being conducted in collaboration with ENGOT and GOG . Patients will be enrolled globally.

P1b/2, N=420, Recruiting, Mersana Therapeutics | Phase classification: P1b --> P1b/2 | N=120 --> 420 | Trial completion date: Dec 2021 --> Dec 2022 | Trial primary completion date: May 2021 --> Jul 2022

P1b, N=120, Recruiting, Mersana Therapeutics | Trial completion date: Dec 2020 --> Dec 2021 | Trial primary completion date: Jul 2020 --> May 2021

Results As of 01-May-2020, 27 pts with ovarian cancer have enrolled: median age was 70 years (range 55 to 85); median prior lines of therapy was 3 (range 1 to 5); >50% had received prior bevacizumab and/or a PARP inhibitor. Funding: Mersana Therapeutics, Inc. Clinical trial identification: NCT03319628.

Altogether, we conclude that the SLC34A2-ROS-HIF-1-induced overexpression of EZH2 promotes colorectal cancer cells proliferation and chemo-resistance to apoptosis. SLC34A2-ROS-HIF-1-EZH2 signaling pathway might serve as a novel therapeutic target against colorectal cancer.

Overall, XMT-1536 treatment demonstrated clinical activity in high grade serous ovarian cancer and NSCLC adenocarcinoma and was generally well-tolerated with no new safety signal trends identified in the EXP. Clinical efficacy and the relevance of NaPi2b expression for treatment with XMT-1536 will be presented. Research Funding: Mersana Therapeutics