Repurposing Neuroactive Drugs in Oncology: A Mini-Review

Cancer is the second leading cause of death in the U.S., leading to the loss of over half a million lives in 2019 alone [1]. While there are many available treatments, one hallmark of lethal forms of cancer is the development of drug resistance. Drug resistance gives rise to an evolutionary arms race between cancer and pharmaceutical companies, which spend billions of dollars each year in research and development attempting to discover new and powerful therapies to treat drug-resistant forms of cancer. One main weakness of developing novel first-in-human therapies in oncology is the high failure rate in clinical trials, with success rates remaining less than 4% for these types of compounds [2]. This low success rate is due to two main factors: 1. lack of efficacy in the target disease, and/or 2. intolerable toxicity. A more promising approach is drug repurposing or repositioning, which is a strategy for enhancing the value of a drug already used in the clinic for other indications by utilizing it to target diseases other than those it was originally intended to treat. Repurposed drugs, which have a known mechanism of action and toxicological profile, provide a much stronger approach to treat cancers with similar biomarkers and disease mechanisms, due to the probability of higher success rates in clinical trials.


Introduction
Cancer is the second leading cause of death in the U.S., leading to the loss of over half a million lives in 2019 alone [1]. While there are many available treatments, one hallmark of lethal forms of cancer is the development of drug resistance. Drug resistance gives rise to an evolutionary arms race between cancer and pharmaceutical companies, which spend billions of dollars each year in research and development attempting to discover new and powerful therapies to treat drug-resistant forms of cancer. One main weakness of developing novel first-in-human therapies in oncology is the high failure rate in clinical trials, with success rates remaining less than 4% for these types of compounds [2]. This low success rate is due to two main factors: 1. lack of efficacy in the target disease, and/or 2. intolerable toxicity. A more promising approach is drug repurposing or repositioning, which is a strategy for enhancing the value of a drug already used in the clinic for other indications by utilizing it to target diseases other than those it was originally intended to treat. Repurposed drugs, which have a known mechanism of action and toxicological profile, provide a much stronger approach to treat cancers with similar biomarkers and disease mechanisms, due to the probability of higher success rates in clinical trials.
One area of oncology that may greatly benefit from repurposed drugs is the treatment of neuroendocrine tumors (NETs). This difficult-to-treat cancer subtype can arise de novo or can be treatment induced. NETs have both neuronal and endocrine cell properties, expressing neuronal genes and exhibiting a neuronal morphology, while also expressing both neurotransmitter receptors and neurotransmitters such as serotonin (5-HT), neuropeptides, and acetylcholine [3][4][5]. This large shift in cellular characteristics commonly renders them resistant to current cancer therapies. The study of NET biology is an emerging field of cancer research and is vitally important for the development of novel therapeutics. However, the knowledge of neuronal characteristics in NETs provides a unique opportunity for repurposing neuroactive therapies currently used to treat the multitude of neurological disorders ranging Copyright © Tyler Bland MADD.MS.ID.000550. 2(5).2020 from neurodegenerative diseases to pain management. The mini review will focus on select examples of these neuroactive drugs that show promise in repurposing as cancer therapeutics.

Neurological Disorders
Neurological disorders comprise a wide variety of disorders and diseases ranging from neurodegenerative and mental disorders that can affect mood, thinking, and behavior such as Alzheimer's Disease (AD), Parkinson's Disease (PD), depression, and Schizophrenia, to peripheral nervous system disorders such as neurogenic bladder and neurologic bowel disorder.
One promising area for drug repurposing is in mental disorder treatments. Many biomarkers and disease mechanisms seen in mental disorders are also observed in NETs. Depression has been linked to defects in serotonergic (5-HT) signaling leading to treating patients with antidepressant compounds that increase 5-HT tone such as selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), and monoamine oxidase inhibitors (MAOIs). TCA and SSRI treatments have been observed to reduce the incidence of colorectal cancer [6], and MAOIs have demonstrated efficacy in reducing prostate cancer bone metastasis and prolonging survival in mouse models [7]. Conversely, antidepressants have also shown pro-tumorigenic affects. The SSRI fluoxetine (Prozac) has been found to increase the number of brain metastasis in breast cancer due to changes in blood-brain barrier permeability, pro-inflammation, and glial activation in the brain [8].
While 5-HT is one of the main neurotransmitters involved in depression, another biogenic amine neurotransmitter, dopamine, plays a crucial role in PD. Treatments for PD include L-Dopa and carbidopa which are agonists for dopamine receptors and act to overcome the loss of dopaminergic neuronal signaling in PD patients. Dopamine receptor expression and signaling has been observed in NETs and suggests a therapeutic approach to modulate dopaminergic signaling in these tumors [9]. Carbidopa has shown promise suppressing pancreatic cancer growth in preclinical studies [10], while no effect was seen in breast cancer and melanoma [11].
Another area of neuroactive drugs that show promise as NET therapies are those used to treat psychiatric disorders, with multiple antipsychotics showing anti-tumor effects in preclinical studies. With epidemiological studies showing an inverse relationship between schizophrenia treatments and cancer incidence, many studies have investigated the potential of these compounds as primary cancer treatments [12]. Men undergoing long-term treatment with the schizophrenia drug haloperidol have a reduced risk of developing prostate cancer with in vitro evidence suggesting haloperidol may reduce prostate cancer cell growth [13]. The schizophrenic and major depressive disorder drug aripiprazole (Abilify) reduces cell proliferation and tumor growth of glioma, gastric cancer, and colon cancer [14]. Another schizophrenic drug, sertindole, also shows promise in treating breast and gastric cancers [15,16].
Even compounds that do not have psychological activities but affect peripheral nervous system disorders have shown promise for treating cancer. Overactive parasympathetic signaling is implicated in neurogenic bladder and neurologic bowel disorder, leading to the prescription and treatment with anticholinergics [17,18]. These therapies have demonstrated efficacy in treating a variety of cancers including lung, colon, bladder, and prostate cancers [5,19,20].

Analgesics
An unfortunate symptom of many cancers is the incidence of chronic pain, either due to the cancer itself or as a side effect of many cancer therapies. Many patients are prescribed analgesics, or antinociceptive medications, to prevent or dampen the nociceptive signal from the brain. Many of these therapies act directly on peripheral and central nervous systems. While they show strong efficacy modulating pain sensation, they also may be useful in treating tumors directly. Analgesics fall into two categories: 1. opioids, and 2. non-opioids.
The first, and probably most well-known class of analgesics, is opioids. These drugs treat pain sensation by blocking neuronal signaling involved in nociception through activating opioid receptors. The anti-tumor effects of opioids are controversial [21], though some studies have reported the ability of opioids to decrease tumor growth. For instance, morphine treatment was found capable of suppressing lung cancer cell proliferation [22], while no effect was seen in breast tumor growth [23], suggesting that morphine treatment may be beneficial in a cancer type-specific manner.
Non-opioid analgesics are also used to treat pain and have a mechanism of action other than regulating opioid receptor activity. One example is lidocaine, which is commonly used as a local anesthetic to treat dermal and oral pain and has been shown to prevent breast cancer progression and metastasis [24][25][26], prevent the progression of retinoblastoma [27], and induce cell cycle arrest in colon cancer [28]. The analgesics metamizole and paracetamol have been shown to inhibit pancreatic cancer growth [29] while metamizole and acetaminophen exert cytotoxic effects in colon cancer [30]. Synthetic cannabinoids such as nabilone and cannabidiol also show promise as cancer therapeutics [23], yet this remains controversial [31,32].

Conclusion and Future Perspective
Overall, neuroactive drugs used in the clinic to treat neurological disorders and pain management represent a promising class of drugs for repurposing as cancer therapeutics. NETs show a remarkable similarity of genotype and phenotype with neurons as directly evidenced by common biomarkers seen in both cell types. This provides strong evidence that neurotherapies will show efficacy in these cancer types. While some evidence already exists in this arena, much more still needs to be explored about these difficult-to-treat cancers, particularly cancer type-specific responses to individual neurotherapy given opposite treatment Copyright © Tyler Bland MADD.MS.ID.000550. 2(5).2020 outcomes in different types of cancer for some neurotherapies. Precision medicine may be a potential approach to determine the type of therapy tailored for individual patients by examining the biomarkers expressed in a patient's tumor for prescribing the corresponding treatment. The repurposing nature of these therapies will provide a quick translational timeframe due to the already known mechanism of action and toxicology. We anticipate that many of these neuroactive drugs will enter the oncology market in the near future and will provide treatments to extend the survival of many patients who suffer from difficult-to-treat cancers with limited viable therapeutic options.