P3, N=740, Not yet recruiting, Tempest Therapeutics

Compound 3f induced a concentration-dependent activation of caspases and cell-cycle arrest in both colorectal cancer models. Docking experiments were also performed to shed light on the putative binding mode of this novel class of dual PPARα/γ antagonists.

TPST-1120 was well tolerated as monotherapy and in combination with nivolumab and the combination showed preliminary evidence of clinical activity in PD-1 inhibitor refractory and immune compromised cancers.

There is a paucity of treatment options for patients with stage IV RCC post anti-PD1 and anti-VEGF therapies. Novel therapies on this clinical scenario are needed. On this abstract we showed radiographic and pharmacodynamic data on patients with RCC who achieved a clinical partial response by RECIST on the phase I clinical trial TPST1120-001.

P1, N=38, Completed, Tempest Therapeutics | Active, not recruiting --> Completed | N=138 --> 38 | Trial completion date: Jun 2024 --> Sep 2022

TPST-1120 was well tolerated and showed signs of activity in a phase I trial as monotherapy and in combination with nivolumab (NCT03829436). TPST-1120 treated patients with PR demonstrated fatty acid oxidation perturbations and immune gene expression changes as potential biomarkers of clinical benefit. Increased frequencies of responding patients bearing PI3K pathway or IDH mutations may reveal populations likely to benefit from treatment with TPST-1120. 1.

Moreover, the involvement of Nrf2 and COX2 in IB66-treated MCF7 cell response has been highlighted. The reported data lay the groundwork for the development of alternative targeted therapy involving the Nrf2/PPARα molecular axis, able to overcome BC cell chemoresistance and cause better clinical outcomes, promoting other forms of programmed cell death, such as pyroptosis.

Because other PPARα target genes remained unaffected, these results suggest a highly specific mechanism implicated in FGF21 regulation. We conclude that FGF21 can be specifically modulated by FOXO1 in a PPARα-dependent manner.

On examining the substrate interaction status of AEDs with BCRP, VPA, phenytoin and lamotrigine were found to be potential BCRP substrates...Significance Statement Induction of multidrug transporters at blood-brain barrier can largely affect the bioavailability of the substrate antiepileptic drugs in the brains of patients with epilepsy, thus affecting their therapeutic efficacy. The present study reports a mechanistic pathway of breast cancer resistance protein (BCRP/ABCG2) upregulation by valproic acid in human brain endothelial cells via peroxisome proliferator-activated receptor alpha involvement, thereby providing a potential strategy to prevent valproic acid pharmacoresistance in epilepsy.

Trial Registration TPST-1120 as Monotherapy and in Combination With Nivolumab in Subjects With Advanced Cancers (NCT03829436). Patients with PR demonstrated gene expression changes that implicate immune activation and alleviation of immune suppression as potential biomarkers of clinical benefit. Increased frequencies of responding patients bearing PI3K pathway or IDH mutations may reveal populations likely to benefit from treatment with TPST-1120.

Finally, treatment with OlGly was able also to reduce increased IL-1β induced by MPP in differentiated cells. In conclusion, our results suggest that OlGly could be a promising therapeutic agent for the treatment of MPP-induced neurotoxicity.

However, miR-21 mimics and PPARα antagonists partially antagonized the above effects of melatonin. Our data indicated that melatonin could alleviate cisplatin-induced cell damage through the upregulation of PPARα/FAO.

P1/2, N=320, Recruiting, Hoffmann-La Roche | Trial completion date: Dec 2024 --> Jul 2025 | Trial primary completion date: Dec 2024 --> Jul 2025

Our results suggest that a balanced estrogen level and its action together with proper GPER and PPAR signaling play a key role in the maintenance of testis homeostasis. Moreover, changes in TGF-β and COX-2 expressions (that disrupted estrogen pathway) as well as disturbed GPER-PPAR signaling observed after estradiol treatment may be involved in testicular tumorigenesis.

TPST-1120 is a novel therapy designed to inhibit tumor proliferation and angiogenesis and stimulate anti-cancer immunity through inhibition of PPARα, a key regulator of FAO. The drug is well tolerated as a single agent and in combination with nivolumab. Promising objective responses have been observed in combination with nivolumab in subjects previously refractory to anti-PD-1 therapy, including 2/2 responders in late-line RCC, and a subject with heavily pretreated CCA, a tumor type generally not responsive to anti-PD-1 alone.

P1/2, N=280, Recruiting, Hoffmann-La Roche | Trial completion date: Jul 2024 --> Dec 2024 | Trial primary completion date: Jul 2024 --> Dec 2024

Lastly, we demonstrate that the in vitro anti-tumor effect of GW6471 is off-target. We conclude that dual PPARα/γ antagonism alone is not a viable treatment modality for mesothelioma.

We identified a gene co-expression network with transcription factors PPARα and PPARγ at its centre that was associated with invasive growth of pleural inoculated mesothelioma. However, we demonstrated that the in vitro antitumour effect of GW6471 is off-target and dual PPARα/γ antagonism alone is not a viable treatment modality for mesothelioma.

P1/2, N=280, Recruiting, Hoffmann-La Roche | Trial completion date: Oct 2024 --> Jul 2024

P1/2, N=280, Recruiting, Hoffmann-La Roche | N=100 --> 280 | Trial completion date: Jul 2024 --> Oct 2024 | Trial primary completion date: Oct 2021 --> Jul 2024

P1/2; N=100; Recruiting; Sponsor: Hoffmann-La Roche