Moreover, the cell respiration inhibitor atovaquone (ATO) would be at the tumor sites, effectively inhibiting cell respiration and elevating oxygen content for endogenous O2 conservation...Upon a single laser irradiation, this synergistic PDT, PTT, and the following immunosuppression regulation performance of IrO2@BSA-ATO NGs achieved a superior tumor cooperative eradicating capability both in vitro and in vivo. Taken together, this study proposes an innovative dual-strategy to address the serious hypoxia problem, and this microenvironment-regulable IrO2@BSA-ATO NGs as a multifunctional theranostics platform shows great potential for OS therapy.

P1, N=44, Recruiting, University Hospital Southampton NHS Foundation Trust | Trial completion date: Nov 2023 --> Jul 2025 | Trial primary completion date: Nov 2023 --> Sep 2024

HSA-131I-MIBG is associated with a high DCR in patients with MPPGL, regardless of underlying genetic mutation.

Furthermore, the combination of atovaquone with paclitaxel suppressed gastric cancer growth and improved overall survival in mice. Given that atovaquone is already approved for clinical use, these findings suggest its potential as a valuable addition to the drug arsenal available for treating gastric cancer.

P1, N=42, Not yet recruiting, Merck Sharp & Dohme LLC

P2, N=28, Recruiting, Emory University | Not yet recruiting --> Recruiting

This heightened susceptibility led to the inhibition of tumor growth and the stimulation of an anti-tumor immune response. These findings suggest that repurposing atovaquone for adoptive cell therapy combination therapy holds the potential to enhance treatment outcomes in HCC.

Pathway analysis identified increased oxidative phosphorylation in D816V- and V560G-mutant KIT cells, which was targetable using the inhibitor IACS010759...Phosphoproteome analysis further revealed active kinases such as EGFR, ERK and PKC, which were targetable using pharmacological inhibitors. This study provides a pharmaco-phosphoproteomic profile of D816V- and V560G-mutant KIT cells, which reveals novel therapeutic strategies that may be applicable to a range of cancers.

We also tested atovaquone in combination with anti-PD-L1 in the LLC (lung) and MC38 (colorectal) cancer syngeneic models but, despite causing a considerable reduction in tumour hypoxia, atovaquone did not add any therapeutic benefit to ICB in these models. These results suggest that atovaquone has the potential to improve the outcomes of patients treated with ICB, but predictive biomarkers are required to identify individuals likely to benefit from this intervention.

P1, N=99, Active, not recruiting, Children's Oncology Group | Trial completion date: Sep 2023 --> Sep 2024

The nanomedicine (ATO/SRF@BSA) was developed by loading sorafenib (SRF) and atovaquone (ATO) into bovine serum albumin (BSA). Furthermore, the anti-cancer results showed that ATO/SRF@BSA exhibited tumor-specific killing efficacy, significantly improved the tumor hypoxic microenvironment, and lessened the toxic side effects of SRF. This work presents an efficient and easily achievable strategy for TNBC treatment, which may hold promise for clinical applications.

Case Presentation: A 77-year-old male with history of deep vein thrombosis (DVT), Parkinson's disease, and lumbar radiculopathy on chronic prednisone, presented for progressive generalized weakness, leg pain, and confusion. HLH should be strongly suspected in patients from endemic regions, especially with additional risk factors such as age, genetics, and immunosuppression. Tools such as the HScore and the HLH-2004 criteria can aid in further patient risk stratification. Urgent treatment with steroids and addressing underlying babesiosis with atovaquone, azithromycin, and potentially red blood cell exchange transfusion, remains crucial for preventing decompensation and improving outcomes.

We demonstrate in a real-life clinical setting that all current therapies show reasonable efficacy in preventing disease progression, and this is equally true for patients with germline SDHB mutations.

Markers of lower NET and VMAT2 protein expression are associated with higher likelihood of response to I-MIBG therapy in patients with relapsed/refractory neuroblastoma. Increased VMAT2 protein expression is associated with a more differentiated disease phenotype.

In summary, atovaquone can inhibit the expression of NF-κB (p-P65) and related inflammatory factors by inhibiting the protein expression of p-PDGFRβ, thereby inhibiting colorectal cancer metastasis. Atovaquone may be a promising drug for the treatment of colorectal cancer metastasis.

Acute myeloid leukemia (AML) stem cells (AMLSCs) AMLSCs and residual cytarabine (AraC)-resistant AML cells (constituting minimal residual disease, MRD) thought to be responsible for chemoresistance and treatment failure, were shown to be highly dependent on mitochondrial function for survival and thus are vulnerable to pharmacological blockade of the oxidative phosphorylation (OXPHOS) (Farge et al...Here we evaluated OXPHOS dependency of AML MRD cells and determined impact of OXPHOS blockade on residual AML cells surviving standard chemotherapy (Doxorubicin/AraC, DA)...Next, the efficacy of IACS-010759 together with DA chemotherapy was evaluated in several chemotherapy-sensitive and -resistant animal models in vivo...Nat Med 2023) showed toxicities impeding its clinical utility, our data advocate for combining mitochondrial targeting strategies with chemotherapy as a part of induction and consolidation treatment for improved control of MRD, eradication of AMLSC and extended response duration. Thus, further studies to identify compounds with improved safety profile are warranted.

P1, N=21, Completed, University of Oxford | Active, not recruiting --> Completed | Trial primary completion date: Jun 2023 --> Oct 2023

P3, N=724, Active, not recruiting, Children's Oncology Group | Recruiting --> Active, not recruiting

P=N/A, N=47, Recruiting, Brigham and Women's Hospital | Not yet recruiting --> Recruiting

MIITOP showed acceptable tolerability in this heavily pretreated population and encouraging survival rates in VHR-NBL when followed by busulfan-melphalan.

In this paper, we review the literature data regarding 131-I-MIBG treatment for neuroblastoma, and report on doses and combinations used, tumor responses and toxicity. 131-I-MIBG is very effective against neuroblastoma, in particular if given to patients at diagnosis and in combination with chemotherapy, and it should be included in all induction regimens to improve early responses rates and consequently long-term survival.

NIS acts as a rapid metabolic sensor for drugs that lead to ATP depletion. PET imaging of NIS could facilitate in vivo testing of treatments targeting energetic pathways, determine drug potency, and expedite metabolic drug development.

P=N/A, N=47, Not yet recruiting, Brigham and Women's Hospital

Inhibition of OXPHOS with IACS-010759, a small-molecule inhibitor, resulted in strong growth suppression in vitro and in vivo in a gefitinib-resistant patient-derived xenograft model. Inhibition of OXPHOS with IACS-010759, a small-molecule inhibitor, resulted in strong growth suppression in vitro and in vivo in a gefitinib-resistant patient-derived xenograft model. Collectively, these findings suggest that metabolic reprogramming by the IGF2BP3-COX6B2 axis plays a critical role in TKI resistance and confers a targetable metabolic vulnerability to overcome acquired resistance to EGFR-TKIs in lung cancer.

P2, N=200, Recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: May 2023 --> May 2025 | Trial primary completion date: May 2023 --> May 2025

P1, N=17, Terminated, M.D. Anderson Cancer Center | N=13 --> 17 | Completed --> Terminated; The study was terminated by the Sponsor for apparent lack of effectiveness.

In these conditions, ascorbate synergized with IACS-010759 to kill MYC-overexpressing cells in vitro and reinforced its therapeutic action against human B-cell lymphoma xenografts. Hence, complex I inhibition and high-dose ascorbate might improve the outcome of patients affected by high-grade lymphomas and potentially other MYC-driven cancers.

Assisted by a trained convolutional neural network, drug sensitivity of cells toward an OXPHOS inhibitor, IACS-010759, could be accurately predicted. AI-assisted OXPHOS drug sensitivity assessment could be accomplished within 1 day, enabling rapid and efficient clinical decision support for HCC treatment. The work proposed here serves as a foundation for the patient-based subtype-specific therapeutic research platform and is well suited for precision medicine.

P1, N=21, Active, not recruiting, University of Oxford | Trial primary completion date: Mar 2023 --> Jun 2023

P1, N=99, Active, not recruiting, Children's Oncology Group | Phase classification: P=N/A --> P1

Importantly, the co-administration of trametinib and IACS-010759, a clinical mitochondrial complex I inhibitor that blocks OXPHOS, significantly impeded tumor growth and prolonged mouse survival. Overall, our findings reveal that MEK inhibitor therapy creates a metabolic vulnerability in the mitochondria and further develop an effective combinatorial strategy to circumvent MEK inhibitors resistance in KRAS-driven NSCLC.

She was started on alpha blockade with doxazosin followed by beta blockade with metoprolol for medical management while hospitalized and discharged home with oncology and endocrinology follow-up...There is no curative treatment for metastatic pheochromocytoma and treatment with surgery, Iobenguane I-131, and chemotherapy are available to improve quality of life. Due to the increased risk of recurrence in patients with NF1, a multidisciplinary approach is essential during initial diagnosis and follow-up treatment. Increased post-operative monitoring may be warranted given the higher risk of recurrence in patients with NF1 who are diagnosed with initial pheochromocytoma.

However, studies looking at the combination of immunotherapies with carboplatin and paclitaxel, which are the mainstay chemotherapies for EOC, have not improved progression-free survival rates. We are also monitoring transcriptomic responses of EOC cells treated with atovaquone to identify changes in expression of DAMPs and other immune-activating pathways through RNA sequencing. Our ultimate goal is to test T cell recognition and responses toward atovaquone-treated EOC cells with the intention of utilizing this chemotherapeutic agent as an adjunct to immunotherapeutic efforts for EOC.