Biology subjects

Zubair, A.

Publications and source records attributed to Zubair, A..

4 recordsLinked to original sources

bioRxiv2024

Optimized CART Cell Therapy for Metastatic Aggressive Thyroid Cancer

Most thyroid cancer deaths are attributed to a subset of poorly differentiated, metastatic tumors. To improve treatment options for aggressive thyroid cancers, we developed a novel thyroid-stimulating hormone receptor (TSHR)-targeted chimeric antigen receptor T (CART) cell therapy, which demonstrated antigen-specific activation and antitumor efficacy against TSHR+ cell lines in vitro and in vivo. However, de-differentiated thyroid cancers downregulate TSHR. We therefore developed a potent treatment strategy by combining our novel TSHR-CART cells with mitogen-activated protein kinase (MAPK) inhibitors, which redifferentiate thyroid tumors and upregulate TSHR expression. In patient-derived anaplastic thyroid cancer xenografts, combination therapy of TSHR-CART cells and MAPK inhibitors led to increased TSHR expression on the tumor tissue and significantly enhanced antitumor efficacy and prolonged survival compared to TSHR-CART monotherapy. Based on our data, we are launching a phase I clinical trial for TSHR-CART cell therapy alone or in combination with MAPK inhibitors in patients with metastatic thyroid cancers. STATEMENT OF SIGNIFICANCEPoor target selection and antigen escape limit CART cell efficacy in solid tumors. We developed TSHR-CART cells to treat differentiated thyroid cancers but observed TSHR downregulation in dedifferentiated thyroid cancers. We found that MAPK inhibitors restored TSHR expression and sensitized these cancers to TSHR-CART cell therapy.

immunology↗

bioRxiv2021

Jointly leveraging spatial transcriptomics and deep learning models for pathology image annotation improves cell type identification over either approach alone.

Spatial transcriptomics technologies have recently emerged as a powerful tool for measuring spatially resolved gene expression directly in tissues sections, revealing cell types and their dysfunction in unprecedented detail. However, spatial transcriptomics technologies are limited in their ability to separate transcriptionally similar cell types and can suffer further difficulties identifying cell types in slide regions where transcript capture is low. Here, we describe a conceptually novel methodology that can computationally integrate spatial transcriptomics data with cell-type-informative paired tissue images, obtained from, for example, the reverse side of the same tissue section, to improve inferences of tissue cell type composition in spatial transcriptomics data. The underlying statistical approach is generalizable to any spatial transcriptomics protocol where informative paired tissue images can be obtained. We demonstrate a use case leveraging cell-type-specific immunofluorescence markers obtained on mouse brain tissue sections and a use case for leveraging the output of AI annotated H&E tissue images, which we used to markedly improve the identification of clinically relevant immune cell infiltration in breast cancer tissue. Thus, combining spatial transcriptomics data with paired tissue images has the potential to improve the identification of cell types and hence to improve the applications of spatial transcriptomics that rely on accurate cell type identification.

bioinformatics↗

bioRxiv2021

The chemotherapeutic CX-5461 primarily targets TOP2B and exhibits selective activity in high-risk neuroblastoma.

Survival in high-risk pediatric neuroblastoma has remained around 50% for the last 20 years, with immunotherapies and targeted therapies having had minimal impact. Here, we identify the small molecule CX-5461 as selectively cytotoxic to high-risk neuroblastoma and synergistic with low picomolar concentrations of topoisomerase I inhibitors improving survival in vivo in orthotopic patient-derived xenograft neuroblastoma mouse models. CX-5461 recently progressed through phase I clinical trial as a first-in-human inhibitor of RNA-POL I. However, we also use a comprehensive panel of in vitro and in vivo assays to demonstrate that CX-5461 has been mischaracterized and that its primary target at pharmacologically relevant concentrations, is in fact topoisomerase II beta (TOP2B), not RNA-POL I. These findings are important because existing clinically approved chemotherapeutics have well-documented off-target interactions with TOP2B, which have previously been shown to cause both therapy-induced leukemia and cardiotoxicity--often-fatal adverse events, which can emerge several years after treatment. Thus, while we show that combination therapies involving CX-5461 have promising anti-tumor activity in vivo in neuroblastoma, our identification of TOP2B as the primary target of CX-5461 indicates unexpected safety concerns that should be examined in ongoing phase II clinical trials in adult patients before pursuing clinical studies in children.

cancer biology↗

bioRxiv2017

Suppression of Transposable Elements in Leukemic Stem Cells

Genomic transposable elements (TEs) comprise nearly half of the human genome. The expression of TEs is considered potentially hazardous, as it can lead to insertional mutagenesis and genomic instability. However, recent studies have revealed that TEs are involved in immune-mediated cell clearance. Hypomethylating agents can increase the expression of TEs in cancer cells, inducing viral mimicry, causing interferon signalling and cancer cell killing. To investigate the role of TEs in the pathogenesis of acute myeloid leukaemia (AML), we studied TE expression in several cell fractions of AML while tracking its development (pre-leukemic haematopoietic stem cells, leukemic stem cells [LSCs], and leukemic blasts). LSCs, which are resistant to chemotherapy and serve as reservoirs for relapse, showed significant suppression of TEs and interferon pathways. Similarly, high-risk cases of myelodysplastic syndrome (MDS) showed far greater suppression of TEs than low-risk cases. We propose TE suppression as a mechanism for immune escape in AML and MDS. Repression of TEs co-occurred with the upregulation of several genes known to modulate TE expression, such as RNA helicases and autophagy genes. Thus, we have identified potential pathways that can be targeted to activate cancer immunogenicity via TEs in AML and MDS.

cancer biology↗