Repositioning of drugs for intervention in tumor progression and metastasis: Old drugs for new targets

Abstract

The increasing unraveling of the molecular basis of cancer offers manifold novel options for intervention strategies. However, the discovery and development of new drugs for potential clinical applications is a tremendously time-consuming and costly process. Translating a novel lead candidate compound into an approved clinical drug takes often more than a decade, and the success rate is very low due to versatile efforts including defining its pharmacokinetics, pharmacodynamics, side effects as well as lack of sufficient efficacy. Thus, strategies are needed to minimize time and costs, while maximizing success rates. A very attractive strategy for novel cancer therapeutic options is the repositioning of already approved drugs. These medicines, approved for the treatment of non-malignant disorders, have already passed some early costs and time, have been tested in humans and are ready for clinical trials as anti-cancer drugs. Here we discuss the repositioning of nonsteroidal anti-inflammatory drugs (NSAID), statins, anti-psychotic drugs, anti-helminthic drugs and vitamin D as anti-tumor agents. We focus on their novel actions and potential for inhibition of cancer growth and metastasis by interfering with target molecules and pathways, which drive these malignant processes. Furthermore, important pre-clinical and clinical data are reviewed herein, which elucidate their therapeutic mechanisms which enable their repositioning for cancer therapy and disruption of metastasis.

Introduction

For decades a plethora of drugs have been developed for the treatment of different malignant and non-malignant disorders. In this effort, natural or synthetic compounds were isolated or generated and extensively tested to finally use them for the treatment of a particular disease in the clinic. The process of drug discovery usually starts with the identification of a compound, which has the potential to become an active drug. Such a compound then can enter the very time-consuming and costly process to achieve a validation of the preclinical therapeutic efficacy of a given compound and to perform pharmacokinetics, pharmacodynamics, and toxicity studies before clinical application is anticipated (Fig. 1). Due to the immensely high costs of pre-clinical as well as clinical evaluation over many years, introduction of new drugs for a particular disease including cancer has become a challenging endeavor.

Analyses regarding scientific, clinical, and financial efforts and the respective establishment of a novel drug for routine clinical application revealed a significant decrease in the number of drugs introduced to the clinic (Mullard, 2014, Pammolli et al., 2011, Scannell et al., 2012). The number of novel drugs has halved every nine years during the past 40 years of drug development per billion US dollars invested into research and development. The average time for the development of a novel drug has also increased considerably over time. During the 1990s the average time required from drug discovery to its use in the clinic (market launch) was 9.7 years. This has then increased to almost 14 years from 2000 onwards – and still increases (Pammolli et al., 2011). In addition to this dilemma, the Tufts Center for Study of Drug Development stated that costs for market launch of a new drug in 2014 has increased 1.7-fold compared to the costs required in 2003. These facts reflect the inefficiency of the current drug development process in the developed industrial countries as well as the need of repositioning of already approved drugs.

The general hurdles in drug development also apply to the burning need to develop novel anti-cancer drugs. Here the estimated time required for drug discovery until the drug is approved is ∼8 years, in association with a very low success rate of only 6.7% in phase I clinical trials (Kaitin and DiMasi, 2011, Pantziarka et al., 2014). This is in spite of the tremendous progress made for the identification of novel molecular targets for cancer treatment and the molecular deciphering of signaling pathways, which are essential for tumor development, metastasis, immune surveillance of tumors, drug response or drug resistance mechanisms (Fisher et al., 2013, Gonen and Assaraf, 2012, Huang et al., 2014, Livney and Assaraf, 2013, Niewerth et al., 2015, Zhitomirsky and Assaraf, 2016).

The revolution in computational bioanalyses does further contribute to the acceleration in this field due to improved data mining and correlation analyses, such as correlation of drug response and biomarker expression or of mutations of particular genes. One would expect that with such progress in understanding the molecular basis of cancer biology, drug development of novel anti-cancer agents should be easier, faster and will also promote the entry of novel drugs into clinical application. However, this is hindered by the immense time and financial investment required for introduction of novel drugs into the clinic. In fact, the expected and already observed increase in cancer incidence in association with aging populations in developed countries clearly calls for the development of novel, more targeted, effective, and affordable drugs in the coming years (Vineis and Wild, 2014). This will be essential to better fulfill the modern needs for a more individualized cancer therapy.

Taking into account the various hurdles in the development of novel anti-cancer therapeutics, which aims at new druggable targets but also at already known ones, the use of known compounds does represent an attractive alternative. To achieve this goal, drug repositioning or repurposing came into focus. This approach is based on identification of new indications from already existing approved drugs. More importantly these drugs could be used for the treatment of diseases other than the original indication of the drug. This approach is certainly of particular interest in the search for new drugs for cancer treatment. To achieve this goal more efficiently, the Repurposing Drugs in Oncology (ReDO) project was initiated, to identify candidate drugs with the best potential of clinical use and to bring such drugs to better attention of the basic research and clinical community (Pantziarka et al., 2015, Pantziarka et al., 2014). The ReDO project has defined key criteria, by which such drugs can be efficiently selected as high-potential candidates for further re-evaluation:

• The compound should be well known for many years and widely used in the clinic. Generics of the drug are of advantage.

• The drug should have low toxicity (good toxicology profile), even upon long-term administration.

• A putative mechanism or defined target of action should be known for its use in cancer therapy.

• High-level evidence of anti-cancer activity in vitro as well as in vivo should be shown. In this respect, data generated in syngeneic, orthotopic transplantable models or in genetically engineered mice is of highest rating.

• Anti-cancer activity should be demonstrated at standard dosing at low toxicity.

• The drug of interest with anti-cancer activity should currently not be widely pursued as an active compound in cancer therapy.

Such drugs can be identified via high-throughput screens using small molecule libraries, which incorporate approved drugs of different clinical uses; other than cancer therapy. This is recently supported by various open-access libraries of approved and investigational compounds enabling better drug repositioning, as provided by the National Clinical Guidance Center (NCGC), the Pharmaceutical Collection (NPC) for virtual screening, or the Johns Hopkins Drug Library (JHDL) as another assembly of existing drugs (Huang et al., 2011, Shim and Liu, 2014). Furthermore, knowledge of the molecular structure of target proteins could also be indicative (in silico analysis) that particular compounds might interfere with important functional domains of such target proteins to specifically inhibit their activities. This approach is currently under intense evaluation, called “drug-protein interaction-based repurposing (DPIR)”, analyzing drug-protein interactions for in silico prediction of promising drug candidates (Liu et al., 2014).

The first six compounds the ReDO project has selected for further evaluation are mebendazole (anti-helminthic), nitroglycerin (vasodilator), cimetidine (H₂-receptor antagonist), clarithromycin (antibiotic), diclofenac (nonsteroidal anti-inflammatory drug, NSAID), and itraconazole (anti-fungal), drugs which were not in use for cancer therapy (Pantziarka et al., 2014).

As discussed in the context of drug repositioning, the key questions remain, at which point clinical testing should start for such drugs, if pre-clinical results clearly demonstrate anti-cancer activity? Should the entry level be at clinical phase II or even phase II/III at reduced size of the respective patient numbers required for the respective patient groups in the trial? To maintain the initial advantage of repositioning of drugs during the phases for clinical testing, the enhanced and widely accepted clinical testing is essential.

In this review not only the search for drug repositioning to treat cancer in general is in focus, but also the immense potential of this approach for identification of drugs, which can effectively prevent or inhibit metastasis. This is of particular interest, since for many malignancies patients die of their cancer metastases rather due to the primary tumor. Therefore, drugs which are able to interfere with tumor progression and also with metastasis-associated signaling pathways, are attractive candidates for intense testing. Such drugs could then be used as inhibitors of tumor progression and metastasis, or even as tumor and metastasis preventing drugs in a long-term treatment of defined patient groups.

For such drugs, similar criteria for their selection will apply as defined by the ReDO project:

• The compound should be well known and widely used in the clinic, with a good toxicology profile, particularly for the long-term medication in metastasis prevention settings.

• A putative mechanism or defined target of tumor and metastasis inhibition/prevention should be known.

• High-level in vitro evidence of anti-tumor and anti-metastatic activity as well as in vivo validation should be demonstrated at standard dosing.

  Furthermore:

• The proposed drug candidate might deliberately have multi-target promiscuous properties (polypharmacology), to hit at multiple sites of tumor progression and metastatic signaling pathways.

In the following chapter, different classes of clinically used drugs are introduced and discussed for their application in anti-tumor and anti-metastatic treatments, including their mechanisms of action.