Although surgical intervention serves as the primary treatment for early-stage disease, advanced-stage cases necessitate a variety of oncologic therapeutic approaches, including 131I-MIBG and peptide receptor radionuclide therapy. Herein we report incidental pineal gland activity, represented in 68Ga-DOTATATE PET/CT (SSTR-PET) in 3 pediatric patients diagnosed with stage 4 neuroblastoma, related to the physiological distribution of radiopharmaceuticals.

P1, N=44, Active, not recruiting, University Hospital Southampton NHS Foundation Trust | Recruiting --> Active, not recruiting | Trial primary completion date: Sep 2024 --> May 2025

The nanoparticles are loaded with semiconducting polymers (PFODBT), Atovaquone (ATO), and TMP195 to enhance biocompatibility, targeting ability, and drug uptake and retention at the tumor site...Moreover, the in vivo immune responses are further activated by improving the maturation of dendritic cells, filtration of CD8+ T cells, and depletion of regulatory T cells. This study offers a novel strategy for TNBC therapy by converting the tumor microenvironment from the "cold" into "hot" tumor through multiple synergistic therapies.

P1, N=45, Active, not recruiting, New Approaches to Neuroblastoma Therapy Consortium | Trial primary completion date: Jun 2023 --> Feb 2024

P1, N=18, Recruiting, Emory University | Initiation date: Oct 2024 --> Jan 2025

In HR-NBL, IGRT with reduced margins and a boost dose for residual lesions ≥ 1 cm3 demonstrated excellent locoregional control, comparable to modern literature.

The obtained findings exhibited the high in vitro potency of QBA, especially in combination with atovaquone against T. gondii RH strain tachyzoites. Although apoptosis induction can be suggested as one of the principle mechanisms, more studies are required to elucidate its accurate mechanisms, as well as its efficacy and safety in animal models and clinical settings.

To address this matter, an O2 regulator (SNP@Ato) is designed for breaking chemoresistance and enhancing PDT, which is constructed by loading Atovaquone (Ato) through self-assembly and host-guest interaction between β-cyclodextrin functionalized tetraphenylporphyrin (TPP-CD4) and thioketal-linked camptothecin/azobenzene (Azo-TK-CPT)...Compared with the SNP group without oxygen-regulator, SNP@Ato exhibits a remarkable improvement of the therapeutic effect against hypoxic tumors in vitro and in vivo. This work proposes a novel paradigm for overcoming hypoxia-induced therapeutic resistance.

Overall, 18% of germline SDHB mutation-carriers were diagnosed with PCC, all of which were unilateral. SDHB-associated PCC was associated with advanced and recalcitrant disease and was often MIBG positive. More studies are needed to better understand the clinical behavior of PCC in PGL-4.

P1, N=18, Recruiting, Emory University

18F-FDOPA PET/CT was found to be the superior functional imaging modality, with 100% lesion detection rate when compared to that of 68Ga-DOTATATE, 18F-FDG, 18F-FDA, and 123I-MIBG scans. While patients did not respond to chemotherapy or tyrosine kinase inhibitors, they responded to targeted radiotherapy using high-specific-activity 131I-MIBG (Azedra®) or 177Lu-DOTATATE (Lutathera®).

P1, N=45, Active, not recruiting, New Approaches to Neuroblastoma Therapy Consortium | Trial completion date: Jun 2024 --> Jun 2025

Using the approved antiprotozoal drug and STAT3 inhibitor Atovaquone (Ato) as prototype for a hydrophobic small molecule, we show that Ato-loaded ovalbumin-coated nanocapsules (Ato-nCap) preferentially enter human myeloid cells...By measuring the effect of Ato nanocarriers on induced STAT3 phosphorylation in IL-10-primed human dendritic cells and constitutive STAT3 phosphorylation in human melanoma cells, we demonstrate that the intracellular Ato release is particularly effective from Ato nanocrystals and less toxic than equal doses of free drug. These new nanocarriers thus represent effective systems for intracellular drug delivery.

P2, N=28, Recruiting, Emory University | Trial completion date: Jun 2025 --> Jun 2026 | Trial primary completion date: Jun 2024 --> Jun 2025

PPGLs patients with earlier onset age, SDHB or Cluster 1A-related gene mutations, negative 131I-MIBG imaging, or positive MGMT immunohistochemistry staining tend to have a higher Ki-67 index. Head and neck tumors, though smaller, exhibit a higher proliferation potential.

The metabolic actions of Dpep on glycolysis led us to explore combinations of Dpep with clinically approved drugs metformin and atovaquone that inhibit oxidative phosphorylation and that are in trials for cancer treatment. Dpep showed additive to synergistic activities in all lines tested. In summary, we find that Dpep induces TXNIP in a cell context-dependent manner that in turn suppresses glucose uptake and glycolysis and contributes to apoptotic death of a range of cancer cells.

The combination of AURKA inhibition with 131I-MIBG treatment is active in resistant neuroblastoma models.

Herein, we develop a simple method to integrate both atovaquone (ATO, a mitochondrial inhibitor) and cisplatin within tannic acid (TA)-iron (Fe) networks coated with hyaluronic acid (HA) for targeted magnetic resonance (MR) imaging-guided chemo-chemodynamic synergistic therapy. Furthermore, TFP@ATO-HA exhibited a r1 relaxivity of 2.6 mM-1 s-1 and targeted MR imaging of 4T1 tumors. Dual drug-loaded metal-phenolic networks can be easily prepared and act as effective theranostic nanoplatforms for targeted MR imaging and synergistic chemo-chemodynamic therapy.

This comprehensive review delves into the current practice, discussing the use of the various Food and Drug Administration-approved SSTR-agonist positron emission tomography tracers and the predictive imaging biomarkers, and elaborating on 177Lu-DOTATATE peptide receptor radionuclide therapy including the evolving areas of posttherapy imaging practices and peptide receptor radionuclide therapy retreatment. SSTR-targeted imaging and therapy can also be used in patients with PPGL; however, this patient population has demonstrated the best outcomes from norepinephrine transporter-targeted therapy with 131I-metaiodobenzylguanidine. Metaiodobenzylguanidine theranostics for PPGL will be discussed, noting that in 2024 it became commercially unavailable in the United States. Therefore, the use and reported success of SSTR theranostics for PPGL will also be explored.

CDK12 deficiency promotes castration-resistant prostate cancer (CRPC) progression by reprogramming cellular metabolism. CDK12 deficiency in CRPC leads to a more active mitochondrial electron transport chain (ETC), ensuring efficient cell energy supply. CDK12 phosphorylates RNA Pol II to ensure the transcription of ACSL4 to regulate ferroptosis. Mitochondrial ETC inhibitors exhibit better selectivity for CDK12-deficient CRPC cells, offering a promising new therapeutic approach for this subtype of CRPC patients.

P1/2, N=0, Withdrawn, David Bushnell | N=50 --> 0 | Trial completion date: Oct 2025 --> Apr 2024 | Recruiting --> Withdrawn | Trial primary completion date: Oct 2025 --> Apr 2024

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.