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Despite the fact that many types of drugs work by blocking a G-protein-coupled receptor (GPCR), there are currently no approved cancer drugs that work this way. The existing scientific literature includes published papers, which observe that dopamine receptors have an effect on cancer but this connection raises a few key questions.

1.  Does it make sense that neurotransmitter pathways have a role in oncology?

Dopamine Receptor D2 (DRD2) is overexpressed by several types of human cancer and its inhibition is associated with anti-cancer activity. This is documented by studies describing: 1) elevated DRD2 expression in malignant cells compared with normal cells; 2) preclinical studies documenting the antitumor effects of antagonizing DRD2 signaling; and 3) observed associations of cancer incidence with other diseases that affect dopamine receptor signaling.

First, there is a large body of literature indicating elevated DRD2 expression in malignant cells compared with normal cells in several tumor types. Moreover, this overexpression tends to increase with the stage of the disease. This is consistent with finding that DRD2 impacts several signaling cascades that are intimately involved in cancer cell survival, angiogenesis, migration, and metastasis. See Table 1 for studies indicating elevated DRD2 expression in malignant cells compared with normal cells.

Second, there are a large number of preclinical studies documenting the antitumor effects of antagonizing DRD2 signaling, either through genetic or pharmacological inhibition (Table 2). The most thoroughly investigated is thioridazine, an antipsychotic DRD2 antagonist that in preclinical models is pro-apoptotic, anti-angiogenic, and depletes cancer stem cells in several tumor types. Several signaling pathways have been implicated in the antitumor mechanism of DRD2 inhibitors, including downregulation of Ras signaling and upregulation of oxidative stress.

Third, there are meta-analyses that have examined cancer incidence in populations with dysregulated dopamine receptor signaling and have found that dopamine blockade leads to lower levels of cancer. For example, a meta-analysis of patients with Parkinson’s disease (Bajaj et al, 2010), where dopamine is downregulated (effectively antagonized), revealed a significantly reduced incidence of most cancers.  Interestingly, while this association was true for most solid and hematological malignancies, the exceptions – including melanoma and thyroid cancers – are tumors with low expression of DRD2. A similar analysis of schizophrenic patients where dopamine is upregulated, found an increase in cancer incidence that is reversed in patients who are compliant with treatments that antagonize dopamine (Dalton et al, 2005).

2.  How is dopamine receptor signaling involved in cancer?

DRD2 is a member of the dopamine receptor family that is grouped into two classes: the D1-like receptor class composed of DRD1 and DRD5 and the D2-like receptor class composed of DRD2 (with the highest affinity for dopamine), DRD3, and DRD4. All of the dopamine receptors are G protein-coupled receptors (GPCRs), whose signaling is primarily mediated by interaction with and activation of heterotrimeric GTP-binding proteins (G proteins). GPCRs control pro-survival signaling pathways (e.g. ERK and Akt) that are broadly important in human cancer.

The D2-like receptor family is coupled to G specific types of G proteins that mediate their signaling. One type of G protein coupled to D2-like receptor activation acts as an inhibitor

of adenylate cyclase, a key enzyme involved in the synthesis of cyclic AMP (cAMP) that affects many intracellular signaling pathways. By contrast, the D1-like family of receptors is coupled to a different type of G protein that stimulates adenylate cyclase and thus opposes D2-like receptor signaling.

Figure 1. DRD2 signaling upon stimulation involves downregulation of cyclic AMP and upregulation of Ras signaling. Credit: Oncoceutics

Activation of D2-like receptors also stimulates ERK and Akt signaling that promotes cancer cell survival. The mechanism that couples D2-like receptors to this signaling is complex and differs depending on cell type, but often involves scaffold proteins such as KSR-1 or β-arrestin that are recruited to the activated GPCR and facilitate kinase signaling cascades.

Oncoceutics’ lead compound ONC201 has demonstrated significant anti-tumor activity in both pre-clinical and clinical studies dating back to 2011.  Recently, it has been demonstrated that ONC201 is a selective antagonist of DRD2, a GPCR that is a dopamine receptor, and that this DRD2 antagonism is responsible for antitumor activity of ONC201.

This makes ONC201 the first clinical molecule for oncology that targets neurotransmitter pathways.

Table 1. Studies indicating elevated DRD2 expression in human cancers

 

Tumor Type(s)

Conclusion

Reference

Small cell lung cancer

Elevated plasma dopamine & dopamine receptor expression in SCLC

Cherubini et al, 2016

Cervical cancer

DRD2 is associated with cervical cancer progression; cervical cancer cells respond to thioridazine

Mao et al, 2015

Neuroendocrine tumors

DRD2 is expressed in 35% of GI neuroendocrine neoplasms

Diakatou et al, 2015

Lung cancer

DRD2 is expressed in 74% of lung carcinoids

Kanakis et al, 2015

Meningioma

DRD2 was expressed in 93% of meningiomas

Trott et al, 2015

Pituitary adenoma

DRD2 is the highest expressed dopamine receptor in pituitary adenomas

Gabalec et al, 2015

Pheochromocytoma

DRD2 mRNA & protein is expressed in pheochromocytomas

Saveanu et al, 2013

Neuroendocrine tumors

11/17 neuroendocrine tumors expressed DRD2

Pawlikowski et al, 2011

Pheochromocytoma/paraganglioma

DRD2 is highly expressed in pheochromocytomas and paragangliomas

Saveanu et al, 2011

Neuroendocrine tumors

DRD2 was expressed in gastroenteropancreatic neuroendocrine tumors

Diakatou et al, 2011

Cholangiocarcinoma

Elevated Dopamine secretion and DRD2 expression

Coufal M et al 2010

Neuroendocrine tumors

DRD2 is expressed in the majority of low and intermediate grade neuroendocrine tumors

Srirajaskanthan et al, 2009

Corticotroph adenomas

DRD2 is expressed in corticotroph adenomas

de Bruin et al, 2009

Colon cancer

DRD2 genotypes can increase risk of colon cancer recurrence

Murphy et al, 2009

Neuroendocrine tumors

DRD2 is expressed in neuroendocrine tumors, more prevalent in aggrestive tumors

Grossrubatscher  et al, 2008

Table 2. Studies indicating anti-tumor efficacy of DRD2 antagonists in preclinical models

 

Tumor Type(s)

Conclusion

Reference(s)

Solid tumors

Trifluoperazine has anti-metastatic properties

Pulkoski-Gross et al, 2015

Breast cancer

DRD2 agonists or antagonists kill MCF7 cells

Pornour et al, 2015

Glioblastoma

Genetic knockdown or haloperidol has anticancer activity in GBM

Li et al, 2014

Breast cancer

Thioridazine and doxorubicin possess anticancer activity

Ki et al, 2014

Neuroendocrine tumors

Inhibition of DRD2 and STTR2 has anticancer effects in midgut carcinoid cells

Zitzmann et al, 2013

Neuroblastoma

Sertindole induces neuroblastoma cell death and autophagy

Shin et al, 2012

Hepatocellular carcinoma

DRD2 inhibitors possess anticancer activity

Chen et al, 2011

Neuroblastoma

Halopiredol possesses anticancer activity

Gasso et al, 2012

Small cell lung cancer

Cortexolone possesses anticancer activity

Reina et al, 2011

Glioblastoma

Eticlopride possess anticancer activity

Visnyei et al, 2011

Prostate & NSCLC

Inhibition of DRD2 and STTR2 has anticancer effects

Arvigo et al, 2010

Cholangiocarcinoma

DRD2 antagonism reduces dopamine-mediated tumor cell proliferation

Coufal M et al 2010

Glioblastoma

Thioridazine possesses anticancer activity

Cheng et al, 2015

Cervical cancer

Mao et al, 2015

Murine breast cancer

Yin et al, 2015

Hepatocellular carcinoma

Lu et al, 2015

Ovarian cancer

Park et al, 2014; Rho et al, 2011; Byuen et al, 2012;

Gastric cancer

Mu et al, 2014

Nasopharyngeal carcinoma

Lan et al, 2014

Breast cancer & leukemia

Sachlos et al, 2012

Cervical & endometrial cancer

Kang et al, 2012

Lymphoma

Spengler et al, 2011

Glioma and neuroblastoma

Gil-Ad et al, 2004

Lymphoma and leukemia

Zhelev et al, 2004

Breast cancer

Strobl et al, 1990

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