Stories of drug repurposing for pancreatic cancer treatment—Past, present, and future

Introduction

Cancer in general is one of the leading causes of mortality worldwide [ ]. Pancreatic ductal adenocarcinoma (PDAC), as the most frequent malignant tumor of the pancreas, has not a high incidence on a global level. However, it is projected to become the second leading cause of cancer-related death in particular in the United States and in Europe by 2030 [ ]. At the time of diagnosis, only about 10% of all PDACs are local disease with a 32% 5-year survival rate and 29% are regional disease with a 12% 5-year survival rate [ ] Some of the latter group will become eligible for surgery after upfront chemotherapy. Unfortunately, the majority of patients (52%) are diagnosed with distant stage disease and will undergo relatively inefficient systemic therapy regimens, such as modified FOLFIRINOX (FFX; fluorouracil, folinic acid, irinotecan, oxaliplatin) or gemcitabine (GEM) plus nanoparticle albumin-bound paclitaxel (nab-paclitaxel; GnP) with a 5-year survival rate of currently only 3% at the moment [ , ]. Although lately, some progress can be seen, due to the mentioned facts, PDAC patients usually still encounter a dismal prognosis at the time of diagnosis, and thus, the 5-year overall survival (OS) of all PDAC patients is about 8% [ ]. Prevention is difficult in this neoplasm, where only few factors associated with higher incidence are known and only a small number of specific risk factors are tightly linked to its occurrence. Randomized screening of patients at high risk, such as those with a family history of PDAC, by MRI or endoscopic ultrasound has not yielded the expected success [ ]. Similarly, current screening methods do not permit early discovery, which is in part due to the difficult accessibility of the pancreas, although tremendous efforts are invested into approaches that might help to delineate the disease at earlier, and therefore, treatable stages of disease, such as analysis of exosomes or other liquid biomarkers [ ].

At the same time, remarkable energy is being invested in drug discovery, not only for PDAC but also anticancer strategies in general. Research spending of private and public foundations (e.g., National Institutes of Health, Deutsche Forschungsgemeins, etc.) is rising, biotechnology companies or spin-offs are being launched, and established pharmaceutical companies are investing increasingly higher budgets on drug development. Many of those ventures have not translated into more or better drugs to the extent of the invested resources. Estimates of different studies show that research and development expenditures for a new drug might accumulate up to $2.6 billion or higher [ ]. Moreover, from basic research to the eventual FDA filing, it is a lengthy process and might take anywhere from 9 to 20 years ( Fig. 9.1 ). Apart from the economic and long-lasting efforts, respectively, high failure rates add up to a very interminable route, and so, overall, only about 5%–12% of all drugs that enter Phase I clinical trials ultimately receive FDA approval ( Figs. 9.1 and 9.2 ) [ , ].

Drug repurposing is therefore an increasingly attractive field for alternative drug development. This is especially appealing because, in general, clinical trials are designed to test very specific questions and narrow hypotheses but cannot focus on and/or expose unexpected benefits [ ]. Moreover, patients who might profit in a different way might not even be included in initial trials, e.g., children, pregnant women, or elderly people. The latter two issues could explain the high failure rate in clinical trials in part. On the other hand, estimates attribute secondary indications to about 90% of all approved drugs because of molecular origins that different diseases have in common, which makes it highly attractive to “teach new tricks to old dogs” [ ]. In this regard, drug repurposing or its alternative terms (“new uses for old drugs,” “drug repositioning,” “drug reprofiling,” “therapeutic switching”) have gained considerable attention not only in the field of cancer but also in medicine in general. In summary, this terminology in principal refers to identifying or developing new uses for existing or abandoned pharmacotherapies [ ]. In this chapter, we will briefly summarize common strategies toward drug repurposing in general and discuss successful examples in medicine. In the main part, we focus on repurposing approaches in the past, present, and future in PDAC. For the scope of this chapter, medical device repurposing will not be discussed.

General strategies toward drug repurposing

To discover new purposes for established drugs, different routes have been taken historically. The first approach relies on ongoing basic research and scientific discovery of novel mechanisms of action. In this regard, after the introduction of a drug or device, investigations might reveal the dependence of a different tumor on the same pathway that could then lead to the off-label use of a previously well-established drug. A prime example for that is the expansion of imatinib, originally developed for the treatment of chronic myelogenous leukemia (CML) to other cancer types on the basis of common principal pathways [ , ].

Second, a translational way of discovery depends on the understanding of the pathophysiologic basis of how a drug works. With that, scientists can widen the search for additional applications of a drug to completely different conditions with yet the same mechanism. For instance, beta-adrenergic antagonists or beta-blockers, originally developed to treat to treat angina and cardiac arrhythmias [ , ], have also been applied to alleviate performance anxiety or essential tremor [ ].

Third, clinical observations might help to understand additional and unrecognized (positive) side effects of FDA-approved drugs. For example, bupropion use could be linked to easing smoking cessation but was originally developed as an antidepressant drug [ ]. In a similar way, sildenafil was developed to treat angina pectoris and arterial hypertension. During early phase studies, it was discovered that erectile dysfunction could be significantly improved by its application [ ].

Combining the abovementioned pathways with cutting-edge techniques, such as high-throughput screening as well as computational approaches, might lead to reasonable and modern ways to repurpose drugs to other diseases or vice versa. Ideally, Connectivity Maps of drugs or even drug pipelines, diseases and their most abundant pathways, and genes of the respective tumor would be created. The obtained data could be challenged against each other, evaluated with phenotypic screening in modern models of disease (among others, patient-derived xenografts [PDX], mouse avatars or patient-derived organoids [PDO]), and personalized candidate drugs would be proposed by bioinformatics and/or artificial intelligence (AI) ( Fig. 9.2 ). In this regard, PDOs have the advantage of accelerated assessment of individual neoplastic cell dependencies and drug responses of the pipeline. Also, they can be transplanted into mice with various genetic backgrounds to investigate interactions with the TEM [ ]. Genetically engineered mouse models, including CRISPR/Cas9-edited animals, could serve as avatars to novelties of single and combination therapies as suggested by the drug pipeline [ ]. Genomic alterations often prioritize driver pathways on which the tumor becomes dependent. This dependence can—in theory—be exploited for significant cancer viability inhibition. Moreover, genomic data or gene expression signatures could help to refine data and hence classify additive effects of potential combinations of clinically useful treatment options by prioritizing therapeutic vulnerabilities or helping to identify suitable biomarkers.

Perspectives of drug repurposing and successful examples

Recent history of drug repurposing is rich in examples of successfully repurposed drugs including some with initial failure or even severely harmful side effects.

In the field of cardiology, several blockbuster drugs have been developed to help people with different ailments such as clogged coronary arteries, arrhythmia, or arterial hypertension. In this regard, the calcium channel blocker verapamil was introduced in 1963 for the treatment of angina pectoris; however, through basic and translational strategies as described in Section General strategies toward drug repurposing , pathologies in calcium channel functioning were shown to be involved in many other medical conditions, such as esophageal spasms, peripheral vascular disease, preterm labor, hypertension, and even migraine. For all of those ailments, verapamil is in use nowadays in a repurposed manner [ ]. Another prime example in the field of cardiology is the widened use of beta-blockers, initially introduced to treat tachycardic conditions, but with remarkable effects for patients with performance anxiety or essential tremor [ ]. Not only that, but as we will discuss later, beta-blockers might also be very useful in the field of oncology to treat tumors that thrive on sympathetic, adrenergic signaling networks [ ].

Last, the phosphodiesterase inhibitor sildenafil (Viagra) was originally developed for coronary artery disease and angina pectoris, which was ineffective. However, clinical testing showed relevant side effects that were fully exploited by repurposing of the drug in order to improve male erectile disfunction and pulmonary arterial hypertension. It has become a blockbuster drug of its own ever since its release in 1998 [ ].

A notable example of initial failure having at first had teratogenic side effects to unborn babies is thalidomide. Initially developed as a sedative drug in the early 1960s, it proved to cause severe malformations if taken during pregnancy [ ]. Nevertheless, basic, translational, and clinical scientific approaches showed its clinical benefits in treating leprosy (FDA approval in 1998) and mechanistically through inhibition of TNF-α as an antitumorigenic drug for multiple myeloma as well as rheumatoid arthritis [ ].

Many other interesting examples of successful drug repurposing are summarized in Table 9.1 below.

Drug repurposing strategies in pancreatic cancer (PDAC)

This section reviews strategies that are being applied to the specific purpose of identifying helpful drugs for developing novel approaches toward PDAC treatment. We include trends of both academic institutions and pharmaceutical industry and try to corroborate our statements with prominent case studies of past and present.

Interestingly, exploration of scientific search engines revealed only a small number of hits using the search terms “drug repurposing” and “pancreatic cancer” or “drug repositioning” and “pancreatic cancer” ( Fig. 9.3 ), which emphasizes the enormous potential that these approaches might still promise. However, even in the field of pancreatic cancer, an increase in publications over the last 3–4 years could be noticed and we have reviewed some of those trends before ( Fig. 9.3 ) [ , ].

Last, this section will include a subjective outlook on future repurposing strategies and fields that we consider promising with substantial opportunities of improving medical treatment for patients with PDAC.