Biology subjects

Pal, I.

Publications and source records attributed to Pal, I..

4 recordsLinked to original sources

bioRxiv2024

PRECLINICAL DEVELOPMENT OF A ROMIDEPSIN NANOPARTICLE DEMONSTRATES SUPERIOR TOLERABILITY AND EFFICACY IN MODELS OF HUMAN T-CELL LYMPHOMA AND LARGE GRANULAR LYMPHOCYTE LEUKEMIA

Histone deacetylase (HDAC) inhibitors are a widely recognized and valued treatment option for patients with relapsed or refractory peripheral T cell lymphomas (PTCL). Romidepsin is a relatively selective Class I HDAC inhibitor originally approved for patients with relapsed or refractory (R/R) cutaneous T cell lymphoma (CTCL) and subsequently R/R PTCL. Unfortunately, the FDA approval of romidepsin for R/R PTCL was withdrawn due to a negative Phase 4 post-marketing requirement (PMR), diminishing further the treatment options for patients with PTCL. Herein we describe the development of a first-in-class polymer nanoparticle of romidepsin (Nanoromidepsin) using an innovative amphiphilic di-block copolymer-based nanochemistry platform. Nanoromidepsin exhibited superior pharmacologic disposition, with improved tolerability and safety in murine models of T-cell lymphoma. Nanoromidepsin also exhibited superior anti-tumor efficacy in multiple models including in vitro T cell lymphoma (TCL) cell lines, ex vivo LGL leukemia primary patient samples, and murine TCL xenografts. Nanoromidepsin demonstrated greater accumulation in tumors and a statistically significant improvement in overall survival (OS) compared to romidepsin in murine xenograft models. These findings collectively justify the clinical development of Nanoromidepsin in patients with T-cell malignancies.

cancer biology↗

bioRxiv2024

Female mice lacking GluA3 show early onset of hearing loss, synaptopathy, and afferent swellings in ambient sound levels

AMPA-type glutamate receptors (AMPAR) mediate excitatory cochlear transmission. However, the unique roles of AMPAR subunits are unresolved. Lack of subunit GluA3 (Gria3KO) in male mice reduced cochlear output by 8-weeks of age. Since Gria3 is X-linked and considering sex differences in hearing vulnerability, we hypothesized accelerated presbycusis in Gria3KO females. Here, auditory brainstem responses (ABR) were similar in 3-week-old female Gria3WTand Gria3KO mice. However, when raised in ambient sound, ABR thresholds were elevated and wave-1 amplitudes were diminished at 5-weeks and older in Gria3KO. In contrast, these metrics were similar between genotypes when raised in quiet. Paired synapses were similar in number, but lone ribbons and ribbonless synapses were increased in female Gria3KOmice in ambient sound compared to Gria3WT or to either genotype raised in quiet. Synaptic GluA4:GluA2 ratios increased relative to Gria3WT, particularly in ambient sound, suggesting an activity-dependent increase in calcium-permeable AMPARs in Gria3KO. Swollen afferent terminals were observed by 5-weeks only in Gria3KO females reared in ambient sound. We propose that lack of GluA3 induces sex-dependent vulnerability to AMPAR-mediated excitotoxicity.

neuroscience↗

bioRxiv2022

Postsynaptic GluA3 subunits are required for the appropriate assembly of AMPA receptor GluA2 and GluA4 subunits on mammalian cochlear afferent synapses and for presynaptic ribbon modiolar-pillar morphological distinctions

The encoding of acoustic signals in the cochlea depends on -amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs), but relatively little is known about their reliance on specific pore-forming subunits. With 5-week-old male GluA3KO mice, we determined cochlear function, synapse ultrastructure, and AMPAR subunit molecular anatomy at ribbon synapses between inner hair cells (IHCs) and spiral ganglion neurons (SGNs). GluA3KO and wild-type (GluA3WT) mice reared in ambient sound pressure level (SPL) of 55-75 dB had similar ABR thresholds, wave-1 amplitudes, and latencies. Ultrastructurally, the IHC modiolar-pillar differences in presynaptic ribbon size and shape, and synaptic vesicle size seen in GluA3WT were diminished or reversed in GluA3KO. The quantity of paired synapses (presynaptic ribbons juxtaposed with postsynaptic GluA2 and GluA4) was similar, however, GluA2-lacking synapses (ribbons paired with GluA4 but not GluA2) were observed only in GluA3KO. SGNs of GluA3KO mice had AMPAR arrays of smaller overall volume, containing less GluA2 and greater GluA4 immunofluorescence intensity relative to GluA3WT (3-fold difference in mean GluA4:GluA2 ratio). The expected modiolar-pillar gradient in ribbon volume was observed in IHCs of GluA3WT but not GluA3KO. Unexpected modiolar-pillar gradients in GluA2 and GluA4 volume were present in GluA3KO. GluA3 is essential to the morphology and molecular composition of IHC-ribbon synapses. We propose the hearing loss seen in older male GluA3KO mice results from progressive synaptopathy evident in 5-week-old mice as increased abundance of GluA2-lacking, GluA4 monomeric, Ca2+-permeable AMPARs.

neuroscience↗

bioRxiv2020

CK1 Delta Is an mRNA Cap-Associated Protein That Drives Translation Initiation and Tumor Growth

Whether translation is differentially regulated across liquid and solid tumors remains poorly understood. Here we report the discovery that Casein Kinase 1 delta (CK1{delta}) plays a key role in regulating translation initiation in blood cancers, but interestingly, not in solid tumors. In lymphomas CK1{delta} is a key positive regulator of 4E-BP1 and p70S6K phosphorylation, assembly of eIF4F, and translation initiation. Furthermore, CK1{delta} is pulled down by m7GTP-agarose that mimics the mRNA m7G cap, consistent with the regulatory role of CK1{delta} in translation initiation. Targeting CK1{delta} using a small molecule inhibitor, namely SR-3029, potently kills lymphoma cell lines and primary lymphoma cells across histology subtypes. While SR-3029 shares with mTORC1 inhibitors the overlapping mechanism of repressing 4E-BP1 and p70S6K/RPS6 phosphorylation, the kinetics of repression is slow with SR-3029 and fast with mTORC1 inhibitors such as Torin-1. Remarkably, it is slower-acting SR-3029, but not fast-acting Torin-1, that kills lymphoma cells consistently across multiple histology subtypes. Proteomics and RNA sequencing studies show that SR-3029 represses the expression of many genes preferentially at the translation step, such as genes in the reactome translation initiation pathway. SR-3029 markedly represses the protein level of the C-MYC oncogene without decreasing its mRNA level. In contrast, Torin-1 fails to reduce the protein level of C-MYC in the same lymphoma cells. While SR-3029 also demonstrates potent activity in select solid tumors, its mechanism of action in the solid tumors is different. In breast cancer cells SR-3029 inhibits nuclear localization of {beta}-catenin but at the same concentrations does not inhibit 4E-BP1 and p70S6K phosphorylation or global protein synthesis. Likewise, SR-3029 does not inhibit nuclear localization of {beta}-catenin in lymphoma cells. Our results indicate that CK1{delta} is an mRNA cap-associated protein and an upstream kinase required for 4E-BP1 and p70S6K phosphorylation. CK1{delta} stimulates assembly of eIF4F and translation initiation, and is a critical driver for tumor growth in blood cancers across multiple histology types. CK1{delta} invokes the alternative mechanism of regulating {beta}-catenin in select solid tumors. Our results indicate that CK1{delta} inhibition is a promising therapeutic strategy in both liquid and solid tumors, and the distinct roles of CK1{delta} in these malignancies may serve as biomarkers to enable precision cancer treatment.

cancer biology↗