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John M Maris

Publications and source records attributed to John M Maris.

9 recordsLinked to original sources
PubMed2025

ImmunoTar-integrative prioritization of cell surface targets for cancer immunotherapy.

MOTIVATION: Cancer remains a leading cause of mortality globally. Recent improvements in survival have been facilitated by the development of targeted and less toxic immunotherapies, such as chimeric antigen receptor (CAR)-T cells and antibody-drug conjugates (ADCs). These therapies, effective in treating both pediatric and adult patients with solid and hematological malignancies, rely on the identification of cancer-specific surface protein targets. While technologies like RNA sequencing and proteomics exist to survey these targets, identifying optimal targets for immunotherapies remains a challenge in the field. RESULTS: To address this challenge, we developed ImmunoTar, a novel computational tool designed to systematically prioritize candidate immunotherapeutic targets. ImmunoTar integrates user-provided RNA-sequencing or proteomics data with quantitative features from multiple public databases, selected based on predefined criteria, to generate a score representing the gene's suitability as an immunotherapeutic target. We validated ImmunoTar using three distinct cancer datasets, demonstrating its effectiveness in identifying both known and novel targets across various cancer phenotypes. By compiling diverse data into a unified platform, ImmunoTar enables comprehensive evaluation of surface proteins, streamlining target identification and empowering researchers to efficiently allocate resources, thereby accelerating the development of effective cancer immunotherapies. AVAILABILITY AND IMPLEMENTATION: Code and data to run and test ImmunoTar are available at https://github.com/sacanlab/immunotar.

Humans↗
PubMed2003

Expression of a MYCN-interacting isoform of the tumor suppressor BIN1 is reduced in neuroblastomas with unfavorable biological features.

PURPOSE: Amplification of the MYCN proto-oncogene is strongly correlated with poor outcome in neuroblastoma (NB), although deregulated MYCN is a potent inducer of apoptosis. BIN1 (2q14) encodes multiple isoforms of a Myc-interacting adaptor protein that has features of a tumor suppressor, including the ability to inhibit Myc-mediated cell transformation and to promote apoptosis. We hypothesized that BIN1 may function as a suppressor gene in NB, because Bin1 is highly expressed in neural tissues and binds the Myc Box motifs that are conserved in MycN. EXPERMENTAL DESIGN: Expression of MYCN, total BIN1, and BIN1 isoforms were determined in 56 primary NBs using the real-time PCR. Expression was correlated with biological and genetic features. To determine the functional significance of BIN1 expression we ectopically expressed BIN1 isoforms in NB cell lines with and without MYCN amplification, and assessed clonogenic growth. RESULTS: Four predominant BIN1 isoforms resulting from alternative splicing of exon 12A (a neural tissue-specific exon) and exon 13 (a Myc-binding domain encoding exon) were variably expressed in the 56 primary NBs. Expression of BIN1 was lower in: NBs with MYCN amplification (n = 10) compared with those without, P < 0.03; in International Neuroblastoma Risk Group high-risk NB (n = 19) compared with low- or intermediate-risk NB, P < 0.01; and in metastatic NB (n = 21) compared with localized NB, P < 0.06. BIN1 inactivation by deletion or genomic rearrangement was identified infrequently. Forced expression of BIN1 isoforms containing the Myc-binding domain (with or without exon 12A) inhibited colony formation in NB cell lines with MYCN amplification (P < 0.01) but not in those without. Forced expression of BIN1 isoforms with a MBD deletion did not inhibit colony formation in any cell line assessed. CONCLUSIONS: These data support that reduced BIN1 expression contributes to the malignant phenotype of childhood NB. As we reported previously, BIN1 may function to circumvent MycN-mediated apoptosis in NBs with MYCN amplification.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Pinhole imaging of 131I-metaiodobenzylguanidine (131I-MIBG) in an animal model of neuroblastoma.

PURPOSE: To evaluate (131)I-MIBG scintigraphic localization of xenotransplanted and spontaneously arising neuroblastomas in murine models of high-risk neuroblastoma. METHODS: Neuroblastoma xenografts were created by inoculation of human neuroblastoma cell suspensions into the subcutaneous flanks of athymic nude mice. In addition, spontaneous paraspinal neuroblastomas were detected by direct palpation in MYCN transgenic mice. After measured tumor volumes exceeded 200 mm(3), each mouse received an intraperitoneal injection of 18 muCi/g (131)I-metaiodobenzylguanidine ((131)I-MIBG). Pinhole scintigraphy was performed to evaluate the MIBG biodistribution and to attempt to visualize the tumors. Each mouse was imaged on a gamma camera equipped with a 3-mm pinhole on one head and an HEGP collimator on the other. RESULTS: Images demonstrated absorption of radiolabeled MIBG and visualization of tumors. Analysis of the images allowed for quantification of relative MIBG uptake and for determination of linear and area measurements of the tumors. CONCLUSION: High-energy pinhole imaging effectively demonstrates uptake of radiolabeled MIBG by human neuroblastoma tumors in murine laboratory models. This technique allows for in vivo assessment of tumor burden. In the future, we plan to use this method to evaluate sensitivity for detecting metastatic spread as well as investigating the therapeutic efficacy of high-dose (131)I-MIBG in combination with radiosensitizing agents.

3-Iodobenzylguanidine↗
PubMed2003

ID2 expression is not associated with MYCN amplification or expression in human neuroblastomas.

MYCN is a biologically and clinically important oncogene in human neuroblastoma as genomic amplification reliably predicts for aggressive tumor behavior and a poor prognosis. However, the mechanism by which MYCN amplification and overexpression contributes to a highly malignant phenotype remains obscure. ID2 is a dominant inhibitor of the RB1 tumor suppressor gene product and recently was suggested to be a direct transcriptional target of MYCN. Overexpression of Id2 protein has thus been postulated to result in functional inactivation of retinoblastoma in MYCN-amplified neuroblastomas, offering a potential explanation for the undifferentiated and highly proliferative nature of most MYCN-amplified neuroblastomas, as well as the paucity of retinoblastoma pathway mutations observed in clinical samples. We therefore sought to determine the likelihood that ID2 overexpression is associated with MYCN amplification and overexpression in human neuroblastoma. ID2 was not differentially expressed in 39 primary neuroblastoma specimens analyzed by oligonucleotide array-based expression analysis, and there was no correlation with MYCN expression levels. ID2 mRNA and protein expression was highly variable and independent of MYCN amplification status and mRNA expression in 10 human-derived neuroblastoma cell lines. In addition, ID2 mRNA expression was not associated with MYCN gene amplification status (P = 0.15) or MYCN expression (r = 0.22) in 131 separate diagnostic primary neuroblastoma samples analyzed by real-time quantitative RT-PCR. These data suggest that transcriptional regulation of ID2 by the MycN oncoprotein is unlikely to be a seminal molecular event resulting in a highly malignant neuroblastoma phenotype.

DNA-Binding Proteins↗
PubMed2002

No evidence for the presence of an imprinted neuroblastoma suppressor gene within chromosome sub-band 1p36.3.

Deletion of the distal short arm of chromosome 1 occurs in 35% of primary neuroblastomas (NBs). These deletions tend to be large and extend to the telomere, but a common region within sub-band 1p36.3 is consistently lost. Despite intensive investigation, no candidate tumor suppressor gene within this region has been shown to undergo tumor-specific mutation consistent with biallelic inactivation. In addition, initial studies demonstrated preferential loss of the maternally inherited 1p homologue in NBs with 1p loss of heterozygosity (LOH) without MYCN amplification. This has led to the widely accepted hypothesis that a genomically imprinted NB suppressor gene is the target of 1p deletion in this subset. To test this hypothesis we have studied 293 primary NBs for LOH within 1p36.3 and determined the parental origin of the deleted 1p homologue. LOH within 1p36.3 was demonstrated in 55 NBs (19%). Of these, 29 occurred in tumors without MYCN amplification: 13 had deletion of the maternally inherited 1p, whereas 16 had deletion of the paternally inherited 1p (P = 0.58). These data strongly refute a parent-of-origin effect for 1p deletions in NB and exclude the existence of an imprinted NB suppressor locus in this region.

Alleles↗
PubMed2002

Evidence for a hereditary neuroblastoma predisposition locus at chromosome 16p12-13.

Hereditary predisposition to develop neuroblastoma (Online Mendelian Inheritance in Man 256700), a pediatric cancer of the sympathetic nervous system, segregates as an autosomal dominant Mendelian trait. We performed linkage analysis on seven families with two or more first-degree relatives affected with neuroblastoma to localize a hereditary neuroblastoma predisposition gene. A single interval at chromosome bands 16p12-13 was the only genomic region consistent with linkage (LOD(MAX) = 3.30 at D16S764). Identification of informative recombination events in linked families defined a 28.0-cM region between D16S748 and D16S769 that cosegregated with the disease in each pedigree. Loss of heterozygosity was identified in 5 of 11 familial neuroblastomas and 68 of 336 nonfamilial neuroblastomas (20.2%) at multiple 16p polymorphic loci. A 14.5-cM smallest region of overlap of somatic deletions was identified within the interval defined by linkage analysis (tel-D16S500-D16S412-cen). Taken together, these data suggest that a hereditary neuroblastoma predisposition gene (HNB1) is located at 16p12-13 and that disruption of this gene may contribute to the pathogenesis of nonfamilial neuroblastomas.

Adrenal Gland Neoplasms↗
PubMed2002

Testing of new agents in childhood cancer preclinical models: meeting summary.

A workshop on pediatric preclinical testing, sponsored by the National Cancer Institute and the Children's Oncology Group Phase 1 Consortium, was held on June 26-27, 2001 in Bethesda, Maryland. Drs. Peter Adamson, Peter Houghton, and Malcolm Smith organized and hosted the meeting. There were 20 participants from 12 institutions. The primary objectives of the workshop included: (a) development of a working inventory of available preclinical models (including human tumor xenografts in immunodeficient mice, transgenic and syngeneic tumors, and selected in vitro models), with a basic understanding of the strengths and weaknesses of each as possible components of a preclinical testing program; (b) identification of the key scientific issues related to establishment of a program for preclinical testing of new agents for their applicability to childhood cancers; and (c) identification of the key infrastructure requirements for a program for preclinical testing of new agents for their applicability to childhood cancers. This report is a synthesis of the workshop's presentations and discussions.

Animals↗