Biology subjects

Sansone, P.

Publications and source records attributed to Sansone, P..

3 recordsLinked to original sources

bioRxiv2025

An Investigation of mini-GRID Radiation therapy with Immune Checkpoint Blockade in a Murine Tumor Model

Spatially fractionated radiotherapy has shown potential to improve therapeutic outcomes possibly with an immunogenic mechanistic component. Here we report on in vivo mouse studies investigating mini-GRID pencil-beam radiotherapy combined with anti-PD-1 immune checkpoint blockade. Methods: GRID therapy was delivered at 225kV using the XStrahl Small Animal Radiation Research Platform with two custom lead mini-GRIDs, each consisting of an array of equally spaced holes: 1 mm diameter with 1mm spacing and 254 {micro}m diameter with 508 {micro}m spacing. GRID dosimetry was characterized using EBT3 film to determine peak-to-valley dose ratios and output. Two studies were performed with C57BL/6J mice bearing subcutaneous LLC1 flank tumors. In the first, mice (n=5/group) were treated in 3 groups with a single fraction: 15 Gy open field, 15 Gy 1 mm GRID, or 24 Gy 1 mm GRID. In the second, mice (n=6-7/group) were treated with fractionated GRID radiotherapy in 5 groups: 15 Gy open field x 3 fractions, 15 Gy hemi-irradiation x 3 fractions, (15 Gy 1 mm GRID x 3 fractions, or 15 Gy 254 {micro}m GRID x 3 fractions. All mice were treated with 200 g anti-PD-1 antibody on days 0, 3, and 6, then weekly until humane endpoint (tumor >15 mm in any dimension or ulceration). Results: Peak to valley ratios were 24.5 {+/-} 0.6 and 19.8 {+/-} 0.7 for the 1 mm and 254 {micro}m GRIDs, respectively. Tumor growth and mean survival times in both studies were significantly shorter for all non-open field arms (p < 0.05; Log Rank for survival; 2-way ANOVA for tumor growth). Conclusions: Two novel mini-GRIDs were characterized and tested in combination with anti-PD-1 therapy. In this study, neither single dose nor fractionated GRID therapy with anti-PD-1 improved tumor growth delay or survival. Similarly, hemi-irradiation resulted in worse tumor control compared to conventional open field radiotherapy.

cancer biology↗

bioRxiv2022

Atm loss does not radiosensitize a primary mouse model of Pten-deleted brainstem glioma

Diffuse midline gliomas arise in the brainstem and other midline brain structures and cause a large proportion of childhood brain tumor deaths. Radiation therapy is the most effective treatment option, but these tumors ultimately progress. Inhibition of the phosphoinositide-3-kinase (PI3K)-like kinase ataxia telangiectasia mutated (ATM), which orchestrates the cellular response to radiation-induced DNA damage, may enhance the efficacy of radiation therapy. Diffuse midline gliomas in the brainstem contain loss-of-function mutations in the tumor suppressor PTEN, or functionally similar alterations in the phosphoinositide-3-kinase (PI3K) pathway, at moderate frequency. Here, we sought to determine if Atm inactivation could radiosensitize a primary mouse model of brainstem glioma driven by Pten loss. Using Cre/loxP recombinase technology and the RCAS/TVA retroviral gene delivery system, we established a mouse model of brainstem glioma driven by Pten deletion. We find that Pten-null brainstem gliomas are relatively radiosensitive at baseline. In addition, we show that deletion of Atm in the tumor cells does not extend survival of mice bearing Pten-null brainstem gliomas after focal brain irradiation. These results characterize a novel primary mouse model of PTEN-mutated brainstem glioma and provide insights into the mechanism of radiosensitization by Atm deletion, which may guide the design of future clinical trials. Brief SummaryWe develop a mouse model of PTEN-mutated brainstem glioma and find that perturbation of the ATM does not enhance radiation efficacy in this model.

cancer biology↗

bioRxiv2021

ERα-LBD, a novel isoform of estrogen receptor alpha, promotes breast cancer proliferation and endocrine resistance

Estrogen receptor alpha (ER) drives mammary gland development and breast cancer (BC) growth through an evolutionarily conserved linkage of DNA binding and hormone activation functions. Therapeutic targeting of the hormone binding pocket is a widely utilized and successful strategy for breast cancer prevention and treatment. However, resistance to this endocrine therapy is frequently encountered and may occur through bypass or reactivation of ER-regulated transcriptional programs. We now identify the induction of a novel ER isoform, ER-LBD, that is encoded by an alternative ESR1 transcript and lacks the activation function and DNA binding domains. Despite lacking the transcriptional activity, ER-LBD is found to promote breast cancer growth and resistance to the ER antagonist fulvestrant. ER-LBD is predominantly localized to the cytoplasm and mitochondria of BC cells and leads to enhanced glycolysis, respiration and stem-like features. Intriguingly, ER-LBD expression and function does not appear to be restricted to cancers that express full length ER but also promotes growth of triple negative breast cancers and ER-LBD transcript (ESR1-LBD) is also present in BC samples from both ER(+) and ER(-) human tumors. These findings point to ER-LBD as a potential mediator of breast cancer progression and therapy resistance. SIGNIFICANCE STATEMENTEndocrine resistant and metastatic breast cancer (BC) is a clinically significant problem. Our study of fulvestrant resistant cancer cells led to the discovery of a novel ER isoform which we call ER-LBD. Encoded by a truncated transcript variant (ESR1-LBD) and lacking the N-terminal domains (activation of transcription and DNA binding), ER-LBD displays a unique role in BC tumorigenesis and progression by mechanisms that may involve metabolic and cell growth advantages, stemness and therapy resistance. Importantly, ESR1-LBD is preferentially expressed in human breast tumor tissues and may be used as prognostic marker in BC.

cancer biology↗