A Drosophila platform identifies a novel, personalized therapy for a patient with adenoid cystic carcinoma

Bangi, Erdem; Smibert, Peter; Uzilov, Andrew; Teague, Alexander; Gopinath, Sindhura; Antipin, Yevgeniy; Chen, Rong; Hecht, Chana; Gruszczynski, Nelson; Yon, Wesley J.; Malyshev, Denis; Laspina, Denise; Selkridge, Isaiah; Wang, Huan; Gomez, Jorge; Mascarenhas, John; Moe, Aye S.; Lau, Chun Yee; Taik, Patricia; Pandya, Chetanya; Sung, Max W.; Kim, Sara; Yum, Kendra; Sebra, Robert; Donovan, Michael; Misiukiewicz, Krzysztof; Ang, Celina; Schadt, Eric E.; Posner, Marshall R.; Cagan, Ross L.

doi:10.1016/j.isci.2021.102212

Cited by 26 publications

(20 citation statements)

References 65 publications

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“…As human genomic data flood the present research landscape with tantalizing associations and clues to disease mechanisms, the challenging task to functionally annotate these genomic variants has become increasingly significant. Research consortia have arisen to tackle the challenges of rare and undiagnosed diseases (57,58,59), joining the efforts of individual labs in parsing the data deluge with experimentation to accelerate therapeutic target and drug discovery for more common diseases as well (37,(60)(61)(62)(63). These collective efforts have begun to bear fruit, and they are not limited to the direct relationship between genotype and phenotype alone.…”

Section: Discussionmentioning

confidence: 99%

Integrated Regulation of Dopaminergic and Epigenetic Effectors of Neuroprotection in Parkinson’s Disease Models

Nourse

Russell

Moniz

et al. 2022

Preprint

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Whole exome sequencing of Parkinson's disease (PD) patient DNA identified single-nucleotide polymorphisms (SNPs) in the TNK2 gene. Although TNK2 encodes a non-receptor tyrosine kinase that has been shown to prevent the endocytosis of the dopamine reuptake transporter (DAT), a causal role for TNK2 in PD remains unresolved. We postulated that specific recessive mutations in patients resulted in aberrant or prolonged overactivity as a consequence of failed negative regulation by an E3 ubiquitin ligase, NEDD4. Interestingly, the sole Caenorhabditis elegans ortholog of TNK2, termed SID-3, is an established mediator of epigenetic gene silencing and systemic RNA interference facilitated by the SID-1 dsRNA transporter. While SID-3 had no prior association to dopamine neurotransmission in C. elegans, we hypothesized that TNK2/SID-3 represented a node of integrated dopaminergic and epigenetic signaling essential to neuronal homeostasis. Using genetic and chemical modifiers, including a TNK2 inhibitor (AIM-100) and NEDD4 activator (NAB2), in bioassays for dopamine uptake or RNAi in dopaminergic neurons of C. elegans, we determined that sid-3 mutants displayed neuroprotection from 6-hydroxydopamine (6-OHDA) exposure, as did wildtype animals treated with AIM-100 or NAB2. Additionally, NAB2 treatment of rat primary neurons correlated with a reduction of TNK2 levels and the attenuation of 6-OHDA neurotoxicity. Notably, CRISPR-modified nematodes engineered with genomic mutations in sid-3 analogous to PD patient-associated SNPs in TNK2 circumvented the resistance to RNAi characteristic of SID-3 dysfunction and furthermore exhibited enhanced susceptibility to neurodegeneration. This study describes a molecular etiology for PD whereby dysfunctional cellular dynamics, dopaminergic, and epigenetic signaling intersect to cause neurodegeneration.

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Section: Discussionmentioning

confidence: 99%

Integrated Regulation of Dopaminergic and Epigenetic Effectors of Neuroprotection in Parkinson’s Disease Models

Nourse

Russell

Moniz

et al. 2022

Preprint

View full text Add to dashboard Cite

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“…A partial response was seen for 12 months, after which relapse occurred. Subsequent resistance was due to new genomic amplifications and deletions ( Bangi et al, 2021 ). However, it must be noted that the patients in these two cases had already been on several different therapy regimens, and their cancer had already metastasized by the time personalized therapy had started.…”

Section: The Use Of Drosophila In Personalized The...mentioning

confidence: 99%

Drosophila melanogaster: A platform for anticancer drug discovery and personalized therapies

et al. 2022

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Cancer is a complex disease whereby multiple genetic aberrations, epigenetic modifications, metabolic reprogramming, and the microenvironment contribute to the development of a tumor. In the traditional anticancer drug discovery pipeline, drug candidates are usually screened in vitro using two-dimensional or three-dimensional cell culture. However, these methods fail to accurately mimic the human disease state. This has led to the poor success rate of anticancer drugs in the preclinical stages since many drugs are abandoned due to inefficacy or toxicity when transitioned to whole-organism models. The common fruit fly, Drosophila melanogaster, has emerged as a beneficial system for modeling human cancers. Decades of fundamental research have shown the evolutionary conservation of key genes and signaling pathways between flies and humans. Moreover, Drosophila has a lower genetic redundancy in comparison to mammals. These factors, in addition to the advancement of genetic toolkits for manipulating gene expression, allow for the generation of complex Drosophila genotypes and phenotypes. Numerous studies have successfully created Drosophila models for colorectal, lung, thyroid, and brain cancers. These models were utilized in the high-throughput screening of FDA-approved drugs which led to the identification of several compounds capable of reducing proliferation and rescuing phenotypes. More noteworthy, Drosophila has also unlocked the potential for personalized therapies. Drosophila ‘avatars’ presenting the same mutations as a patient are used to screen multiple therapeutic agents targeting multiple pathways to find the most appropriate combination of drugs. The outcomes of these studies have translated to significant responses in patients with adenoid cystic carcinoma and metastatic colorectal cancers. Despite not being widely utilized, the concept of in vivo screening of drugs in Drosophila is making significant contributions to the current drug discovery pipeline. In this review, we discuss the application of Drosophila as a platform in anticancer drug discovery; with special focus on the cancer models that have been generated, drug libraries that have been screened and the status of personalized therapies. In addition, we elaborate on the biological and technical limitations of this system.

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“…To overcome this issue, Bangi et al. took a Drosophila -based research approach for a patient with advanced AdCC ( 21 ). They developed a patient-specific transgenic fly strain as a ‘personalized fly avatar’ that modeled the patient’s somatic mutations.…”

Section: Fly Models For Various Cancer Genotypesmentioning

confidence: 99%

Drosophila as a toolkit to tackle cancer and its metabolism

et al. 2022

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Cancer is one of the most severe health problems worldwide accounting for the second leading cause of death. Studies have indicated that cancers utilize different metabolic systems as compared with normal cells to produce extra energy and substances required for their survival, which contributes to tumor formation and progression. Recently, the fruit fly Drosophila has been attracting significant attention as a whole-body model for elucidating the cancer mechanisms including metabolism. This tiny organism offers a valuable toolkit with various advantages such as high genetic conservation and similar drug response to mammals. In this review, we introduce flies modeling for cancer patient genotypes which have pinpointed novel therapeutic targets and drug candidates in the salivary gland, thyroid, colon, lung, and brain. Furthermore, we introduce fly models for metabolic diseases such as diabetes mellitus, obesity, and cachexia. Diabetes mellitus and obesity are widely acknowledged risk factors for cancer, while cachexia is a cancer-related metabolic condition. In addition, we specifically focus on two cancer metabolic alterations: the Warburg effect and redox metabolism. Indeed, flies proved useful to reveal the relationship between these metabolic changes and cancer. Such accumulating achievements indicate that Drosophila offers an efficient platform to clarify the mechanisms of cancer as a systemic disease.

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A Drosophila platform identifies a novel, personalized therapy for a patient with adenoid cystic carcinoma

Cited by 26 publications

References 65 publications

Integrated Regulation of Dopaminergic and Epigenetic Effectors of Neuroprotection in Parkinson’s Disease Models

Integrated Regulation of Dopaminergic and Epigenetic Effectors of Neuroprotection in Parkinson’s Disease Models

Drosophila melanogaster: A platform for anticancer drug discovery and personalized therapies

Drosophila as a toolkit to tackle cancer and its metabolism

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