Biology subjects

Ormond, D. R.

Publications and source records attributed to Ormond, D. R..

5 recordsLinked to original sources

bioRxiv2026

Targeting wild type NTRK decreases brain metastases of lung cancers non-driven by NTRK fusions

The central nervous system (CNS) is a common site of metastatic spread for both non-small cell and small cell lung cancer, yet the therapeutic strategies to prevent and decrease lung cancer brain metastases remain limited. Tyrosine kinase inhibitors have shown promising results in increasing the overall response in brain metastases, owing to their brain penetrance and increased effectiveness; however, their use is limited to the small group of tumors carrying specific oncogenic drivers. Among these, inhibitors with activity against neurotrophic tyrosine receptor kinases (NTRKs) are showing promising effects in reducing CNS metastases in cancers driven by gene rearrangements of these drugs targets. However, wild-type NTRKs are susceptible to activation by their canonical ligands, which are expressed throughout the brain metastatic niche and can, in a paracrine manner, activate NTRK function in cancer cells. Here we show that NTRKs are expressed in primary tumors, brain metastases, and lung cancer cells with various driver mutations expressing wild-type NTRK2 (WT-TrkB). We demonstrate that WT-TrkB activates downstream signaling and proliferation in response to exogenous BDNF and conditioned media from reactive astrocytes known to secrete BDNF in the brain niche. Importantly, the FDA-approved NTRK inhibitor entrectinib blocked BDNF and astrocyte-induced survival pathways in multiple lung cancer cell lines, decreased their proliferation in vitro, and effectively prevented brain metastatic colonization and progression in vivo without significant effects on extracranial disease. Thus, these studies suggest that brain-dependent activation of NTRK is critical for brain metastases of WT-NTRK+ lung cancers, and therefore, NTRK inhibitors can be used to target non-fusion NTRK function to prevent or decrease brain metastases. SIGNIFICANCEThese studies demonstrate that NTRK wild-type receptors are important drivers of brain metastatic colonization and progression in different subtypes of lung cancer, independent of their driver alterations. Thus, they provide rationale to expand the use of FDA-approved NTRK inhibitors with brain penetrance for the prevention of CNS metastases.

cancer biology↗

bioRxiv2026

Estradiol Reprograms Microglia to Create an Immune-Suppressed Niche Permissive to Breast Cancer Brain Metastasis

BackgroundYoung age is an independent risk factor for the development of breast cancer brain metastases (BM). Prior work showed that 17{beta}-estradiol (E2), the predominant premenopausal hormone, promotes BM of tumors intrinsically unresponsive to E2, in part through modulating estrogen receptor-alpha expressing (ER) glial cells. However, how E2 reshapes the brain tumor microenvironment (TME), particularly microglia-mediated immunity, and its impact to BM progression remains unclear. MethodsscRNA sequencing and multiparametric flow cytometry were used to define the impact of E2 and E2-suppression on brain immune-cell populations across different stages of BM progression using spontaneous and experimental models of BM. Depletion of microglia and T cell co-cultures were used to study microglias role in E2-induced BM. The effects of E2-suppression alone or in combination with whole brain radiotherapy were tested in preclinical models mimicking late-stage BM. ResultsE2 repressed immune surveillance and immune activation programs in microglia from early to late stages of brain metastatic progression, suppressing recruitment of effector immune cells to BM. Estrogen suppression, in turn reactivated anti-tumoral signaling in microglia and increased recruitment of effector immune cells to the brain. Microglia from E2-stimulated BM-bearing mice showed decreased ability to induce interferon cytotoxic function and expansion of activated T cells. Conversely, E2-suppression reactivated an effective anti-tumoral response and synergized with RT to significantly decrease BM progression. ConclusionThese findings reveal a previously unrecognized mechanism by which E2 accelerates BC-BM progression through microglial immunosuppression and support evaluation of endocrine therapies as adjunct treatments for ER- brain metastases. Importance of the StudyStandard of care for BM includes stereotactic radiosurgery (SRS) alone or in combination with surgery, systemic chemotherapy or targeted therapies. Our studies show that ovariectomy (which eliminates ovarian E2) and aromatase inhibitors (AIs, which eliminate peripheral E2 synthesis) reduce progression of BM when used in combination with WBRT and in immuno-competent models. We demonstrate E2 promotes an immunosuppressive brain microenvironment from early stages of metastatic progression, in part through modulation of myeloid cells and repression of recruitment of effector T cells to the brain. Thus, these studies suggest that FDA-approved E2-depletion therapies (aromatase inhibitors and selective-estrogen modulators) could be used in combination with brain irradiation to decrease BM progression.

cancer biology↗

bioRxiv2023

Short-term Topiramate treatment prevents radiation-induced cytotoxic edema in preclinical models of breast-cancer brain metastasis

BackgroundBrain edema is a common complication of brain metastases (BM) and associated treatment. The extent to which cytotoxic edema, the first step in the sequence that leads to ionic edema, vasogenic edema and brain swelling, contributes to radiation-induced brain edema during BM remains unknown. This study aimed to determine whether radiation-associated treatment of BM induces cytotoxic edema and the consequences of blocking the edema in pre-clinical models of breast cancer brain metastases (BCBM). MethodsUsing in vitro and in vivo models, we measured astrocytic swelling, trans-electric resistance (TEER) and aquaporin 4 (AQP4) expression following radiation. Genetic and pharmacological inhibition of AQP4 in astrocytes and cancer cells was used to assess the role of AQP4 in astrocytic swelling and brain water intake. An anti-epileptic drug that blocks AQP4 function (topiramate) was used to prevent cytotoxic edema in models of BM. ResultsRadiation-induced astrocytic swelling and transient upregulation of AQP4 within the first 24 hours following radiation. Topiramate decreased radiation-induced astrocytic swelling, loss of TEER in astrocytes in vitro, and acute short term treatment (but not continuous administration), prevented radiation-induced increase in brain water content without pro-tumorigenic effects in multiple pre-clinical models of BCBM. AQP4 was expressed in clinical BM and breast cancer cell lines, but AQP4 targeting had limited direct pro-tumorigenic or radioprotective effects in cancer cells that could impact its clinical translation. ConclusionsPatients with BM could find additional benefits from acute and temporary preventive treatment of radiation-induced cytotoxic edema using anti-epileptic drugs able to block AQP4 function. Key pointsO_LIRadiation induces cytotoxic edema via acute dysregulation of AQP4 in astrocytes in preclinical models of BM. C_LIO_LIPharmacologic blockage of AQP4 function prevents water intake, astrocytic swelling and restores TEER in vitro. C_LIO_LIPre-treatment with single-dose Topiramate prevents brain radiation-induced brain edema without direct tumor effects in pre-clinical models of BCBM. C_LI IMPORTANCE OF THE STUDYIn this study we describe a novel role for astrocytic swelling and cytotoxic edema in the progression of radiation-induced brain edema during BM treatment. While radiation-induced edema has been fully attributed to the disruption of the blood-brain barrier (BBB) and ensuing vasogenic effects, our results suggest that cytotoxic edema affecting astrocytes in the acute setting plays an important role in the progression of brain edema during BM standard of care. Current standard of care for brain edema involves pre-treatment with steroids and the use of bevacizumab only after clinically significant edema develops. Both interventions are presumed to target vasogenic edema. This study suggests that patients with BM could find additional benefits from acute and temporary preventive treatment of radiation-induced cytotoxic edema using an already FDA-approved anti-epileptic drug. Such early prevention strategy can be easily clinically implemented with the goal of minimizing treatment-related toxicities.

cancer biology↗

bioRxiv2021

The epigenetic evolution of gliomas is determined by their IDH1 mutation status and treatment regimen

Tumor adaptation or selection is thought to underlie therapy resistance of gliomas. To investigate the longitudinal epigenetic evolution of gliomas in response to therapeutic pressure, we performed an epigenomic analysis of 143 matched initial and recurrent patients with IDH-wildtype (IDHwt) and IDH-mutant (IDHmut) gliomas. IDHwt gliomas showed a longitudinally stable epigenome with relatively low levels of global methylation, whereas the epigenome of IDHmut gliomas showed initial high levels genome-wide of DNA methylation that was progressively reduced to levels similar to those of IDHwt tumors. By integrating DNA methylation and gene expression data, adaptive changes of putative master regulators of the cell cycle and of differentiation were seen in IDHmut recurrent tumors. Furthermore, relapses of IDHmut tumors were accompanied by histological progression which in turn influenced survival, as validated in an independent cohort. Finally, the initial cell composition of the tumor microenvironment differed between IDHwt and IDHmut tumors and changed differentially following treatment, suggesting increased neo-angiogenesis and T-cell infiltration upon treatment for IDHmut gliomas. Our study provides one of the largest cohorts of paired glioma samples profiled with epigenomics, transcriptomics and genomics; and our results demonstrate that the treatment of IDHmut gliomas reshapes the epigenome towards an IDHwt-like phenotype. Accordingly, the prevalent practice of early genotoxic treatment in this patient population may need to be revisited.

genomics↗

bioRxiv2021

Longitudinal analysis of diffuse glioma reveals cell state dynamics at recurrence associated with changes in genetics and the microenvironment

To interrogate the factors driving therapy resistance in diffuse glioma, we collected and analyzed RNA and/or DNA sequencing data from temporally separated tumor pairs of 292 adult patients with IDH-wild-type or IDH-mutant glioma. Tumors recurred in distinct manners that were dependent on IDH mutation status and attributable to changes in histological feature composition, somatic alterations, and microenvironment interactions. Hypermutation and acquired CDKN2A deletions associated with an increase in proliferating stem-like malignant cells at recurrence in both glioma subtypes, reflecting active tumor growth. IDH-wild-type tumors were more invasive at recurrence, and their malignant cells exhibited increased expression of neuronal signaling programs that reflected a possible role for neuronal interactions in promoting glioma progression. Mesenchymal transition was associated with the presence of a specific myeloid cell state defined by unique ligand-receptor interactions with malignant cells. Collectively, our results uncover recurrence-associated changes that could be targetable to shape disease progression following initial diagnosis.

cancer biology↗