We previously tested the combination regimen of tubulin inhibitor VERU-111 with vem, as well as USP14 selective inhibitor b-AP15 in combination with vem, both of which have showed profound therapeutic effects in overcoming vem resistance in vitro and in vivo. Interestingly, overexpression of USP14 antagonized all the ferroptosis cascade events induced by MitoCur-1, therefore, we conclude that MitoCur-1 induces ferroptosis through inhibition of USP14. We believe that by inhibition of USP14, vem resistance can be reversed and will finally benefit melanoma patients in future.
4 months ago
Journal
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BRAF (B-raf proto-oncogene) • GPX4 (Glutathione Peroxidase 4) • SLC7A11 (Solute Carrier Family 7 Member 11) • SKP2 (S-phase kinase-associated protein 2) • USP14 (Ubiquitin Specific Peptidase 14)
Preferred frontline treatment relies on anti-HER2 therapies, such as trastuzumab and pertuzumab, combined with microtubule inhibitors, such as taxanes. While sabizabulin shows promising results for treatment in HER2+ breast cancer, we further optimized the structure of sabizabulin to create a new class of anti-cancer molecules: 40a, CH-2-77, and 60c. Based on in vitro data, 60c showed higher potency in HER2+ breast cancer cell lines and was chosen as the lead compound to further study in a paclitaxel-resistant triple negative breast cancer in vivo study where it was able to effectively inhibit primary tumor growth compared to the vehicle group.
This clinical trial demonstrated that chronic oral daily dosing of sabizabulin has a favorable safety profile with significant preliminary cytotoxic and cytostatic antitumor activity. These data support the ongoing Phase 3 VERACITY trial of sabizabulin in men with mCRPC who have progressed on an androgen receptor targeting agent.
Current frontline therapy for HER2+ metastatic breast cancer relies on targeted antibodies, trastuzumab and pertuzumab, combined with microtubule inhibitors in the taxane class (paclitaxel or docetaxel). In vivo, sabizabulin inhibits breast tumor growth in the BT474 (ER+/PR+/HER2+) xenograft model and a HER2+ (ER-/PR-) metastatic patient-derived xenograft (PDX) model, HCI-12. We demonstrate that sabizabulin is a promising alternative agent to target tubulin in HER2+ breast cancer with similar anti-metastatic efficacy to paclitaxel, but with the advantage of oral bioavailability and lower toxicity than taxanes.
Conclusions This clinical trial demonstrated that chronic oral daily dosing of sabizabulin has a favorable safety profile with significant preliminary cytotoxic and cytostatic antitumor activity. These data support the ongoing phase 3 VERACITY trial of sabizabulin in men with mCRPC who have progressed on an androgen receptor targeting agent.
This clinical trial demonstrated that chronic oral daily dosing of sabizabulin has a favorable safety profile with preliminary antitumor activity. These data support the ongoing Phase 3 VERACITY trial of sabizabulin in men with mCRPC.
This clinical trial demonstrated that chronic oral daily dosing of sabizabulin has a favorable safety profile with significant preliminary cytotoxic and cytostatic antitumor activity. These data support the ongoing Phase 3 VERACITY trial of sabizabulin in men with mCRPC who have progressed on an androgen receptor targeting agent.
mCRPC that has progressed following ARTAs and prior to taxane chemotherapy, remains an urgent unmet medical need for patients with advanced disease. Sabizabulin is an exciting first-in-class agent that may add to the armamentarium for the treatment of mCRPC following progression on ARTA’s.
11 (37%) were previously treated with enzalutamide or apalutamide and 8 (27%) with abiraterone as single agents. Conclusions : In this analysis, sabizabulin has demonstrated not only cytotoxic, but also significant cytostatic activity with similar responses in men that have progressed on a single or multiple ARTA agents. Sabizabulin is a novel agent with the potential provide men with mCRPC a well-tolerated chronic treatment cytostatic option after progressing on an ARTA and is being tested in the open Phase 3 VERACITY trial.
11 (37%) were previously treated with enzalutamide or apalutamide and 8 (27%) with abiraterone as single agents. In this analysis, sabizabulin has demonstrated not only cytotoxic, but also significant cytostatic activity with similar responses in men that have progressed on a single or multiple ARTA agents. Sabizabulin is a novel agent with the potential provide men with mCRPC a well-tolerated chronic treatment cytostatic option after progressing on an ARTA and is being tested in the open phase 3 VERACITY trial.
Metastatic prostate cancer that has become refractory to newer generation ARTAs and prior to IV chemotherapy, remains an urgent unmet medical need for patients with advanced disease. Sabizabulin is an exciting first-in-class agent that will add to the armamentarium for the treatment of metastatic castration and ARTA resistant prostate cancer.
The Phase 3, VERACITY registration clinical trial is current ongoing in approximately 45 clinical sites with enrollment anticipated to be completed in 2022 and with unblinded results presented in 2023.
In the phase Ib/II clinical trial, oral 63mg daily dosing has a favorable safety profile and chronic dosing is feasible. Efficacy was observed with PSA declines and long term durable responses. The phase III VERACITY study evaluating sabizabulin in chemotherapy naïve men with mCRPC who have failed an AR targeting agent is ongoing.
Knockout of Skp2 diminished oncogene AKT expression and contributed to the synergistic inhibitory effect of Vem and VERU-111. Our results indicate a treatment combination of VERU-111 and Vem holds a great promise to overcome Vem-resistance for melanoma patients harboring BRAF (V600E) mutation.
8 received prior enzalutamide, 12 abiraterone and 10 both...9/29 (31%) had previously abiraterone, 10/29 (34%)( enzalutmide, 7/29 (24%) both enzalutmide and abiraterone and 4/29 (14%) apalutamide... Based upon this Phase 1b/2 clinical trial, oral VERU-111 has a favorable safety profile allowing for chronic administration and significant and durable antitumor activity. The daily dose of 63mg is being tested in the fully enrolled Phase 2 portion. Oral administration, safe long-term treatment and evidence of antitumor activity highlight a potential prominent role of VERU 111 for the treatment of men with mCRPC who failed an androgen receptor targeting agent.
When tested in a highly paclitaxel-resistant A549/TxR tumor model, VERU-111 is as effective as the parental A549 model in significantly reducing the tumor volume, whereas paclitaxel is essentially ineffective. Collectively, this study showed that VERU-111 is a promising new generation of anti-tubulin agent for the treatment of taxane-resistant lung cancer.
Taken together, our results demonstrate the potential anti-cancer efficacy of VERU-111 in in vitro and in vivo. VERU-111 can be explored as a potent therapeutic agent for the treatment of cervical cancer.