The success story of drug repurposing in breast cancer

Introduction

Breast cancer is the most prevalent cancer in women worldwide, and despite tremendous research efforts, it remains the second leading cause of cancer-related mortalities among women ( https://seer.cancer.gov/data/ ). According to the 2018 GLOBOCAN report, over 2 million new breast cancer incidences and nearly 600,000 deaths were reported globally [ ]. Breast cancer is vastly heterogeneous owing to differences in the underlying molecular architecture among tumor subtypes. These molecular alterations serve as molecular biomarkers that are useful for diagnosing, staging and grading, therapeutic intervention, prognosis and clinical management of recurrent and metastatic cases. The commonly assessed and clinically validated pharmacodiagnostic markers are estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2, also called HER2/neu) [ ].

Breast cancer classification

Several factors influence the prognosis of breast cancer patients, such as the stage of the disease, size of the tumor, molecular subtype, and age at the time of first diagnosis. Breast cancer staging system primarily includes anatomic factors based on TNM classification, tumor size (T), the extent of spread to nearby lymph nodes (N), and metastases of the malignant growth to distant organs (M). Not long ago, American Joint Committee on Cancer recognized and incorporated the prognostic influence of the biologic factors to refine the precision of the breast cancer staging system. This includes accounting for tumor expression of ER and PR, HER2 expression, proliferation (Ki67), and expression-based classification panels like PAM50 into the staging system [ , ]. Based on these markers, breast cancer has been classified broadly into three major clinical subtypes:

(i)
Luminal like, which is further categorized into luminal A: high ER/PR, low proliferation and luminal B: low ER/PR, high proliferation.
(ii)
HER2 like: ER/PR negative, HER2 positive.
(iii)
Basal like: ER/PR negative, HER2 negative, also known as triple-negative breast cancer (TNBC).

Overall, the 5-year survival rates for breast cancer are 91%, 86% after 10 years, and 80% after 15 years. Relative survival rates, however, do not predict individual prognosis as it fails to take into account the genetic variability between patients and the characteristics of the tumor. For instance, metastatic breast cancer (MBC) 5-year survival rates are only 22% [ ]. Depending on the stage of breast cancer, the overall 5-year relative survival rate is 99% for localized disease, 85% for regional disease, and 27% for distant-stage disease. Furthermore, within each stage, the survival varies by tumor size; for regional disease, the 5-year relative survival is 95% for tumors less than or equal to 2.0 cm, 85% for tumors 2.1–5.0 cm, and 72% for tumors greater than 5.0 cm. Among the clinical subtypes, TNBCs accounts for 15%–20% of breast cancers, are often difficult to treat due to lack of surface markers, and are associated with a high rate of recurrence [ ]. TNBC is more common in premenopausal women and those with a BRCA1 mutation. Less than 30% of women with metastatic TNBC survive past 5 years, and almost all die due to their disease [ , ]. Moreover, the remarkable amount of heterogeneity of TNBCs concerning molecular alterations and tumor microenvironment makes it very challenging to target or treat disease.

Current therapies for breast cancer

Generally, breast cancer diagnosis and management rely on clinical assessment of its pathophysiology, tissue sampling, and examining the markers for molecular subtyping of the tumor. Besides, information on the patient's age and general health is also crucial to assess the other comorbidities that might impact choices of therapy. Based on the clinicopathological factors of the tumor and hormone receptor status, there is a range of modalities employed toward treatment including surgery, radiation therapy, systemic pharmacotherapies that include chemotherapy and endocrine therapy, and targeted immune therapies (antibodies against tumors antigens) [ , ]. Breast cancer surgery may be preceded by systemic neoadjuvant therapies to shrink the tumor for effective surgery. For instance, HER2+ breast cancers that are aggressive kind are administered with trastuzumab (Herceptin) and pertuzumab (Perjeta) as neoadjuvant therapy where trastuzumab is continued postsurgery [ , ]. Postsurgery patients undergo radiotherapy and/or chemotherapy to ensure the destruction of remnant micrometastatic cancer cells, thereby reducing chances of remission and thus increasing the overall patient survival [ ].

Pharmacotherapies relies on the status of hormone receptors or target protein–targeted adjuvant (additional) therapies. In case of early stage ER/PR+ breast tumors that have not spread to the lymph nodes, patients are given long-term endocrine therapies such as tamoxifen or aromatase inhibitors together or alone with the surgical resection, depending on the patient's menopausal status [ ]. In case of TNBCs, the common treatment strategies include chemotherapy with taxane and adjuvant treatment with anthracycline and taxane, sometimes in combination with PARP inhibitors [ ] (discussed in detail in Section 6.6.2 ).

It is noteworthy that while these adjuvant systemic chemotherapies are routinely used for early stage ER/PR+ breast cancer patients, not all of them offer long-term survival benefits when compared to the cost of side effects due to overtreatment. To overcome these inadequacies of the conventional methods, genomic assays such as Oncotype DX have been successfully combined with traditional methods that allow clinicians to predict behavior of the cancer, its recurrence, and whether or not chemotherapy will be beneficial for the early stage breast cancer patients. Initially described and introduced into clinical practice in 2004, Oncotype DX is a multigene prognosis assay that predicted recurrence of tamoxifen-treated, node-negative breast cancer [ ]. It analyzes the expression profiles of 21 genes and predicts the disease recurrence by providing a recurrence score ranging between 0 and 100 to early stage breast cancer patients. Oncotype DX assays were validated in ER+ and node-negative breast cancer and have been included in the guidelines of major oncology organization such as National Comprehensive Cancer Network, American Society of Clinical Oncology, and the National Institute for Health and Care Excellence. Several other commercial genomic tests are available to analyze breast cancer tumors, including EndoPredict (Myriad Genetics, Salt Late City, UT, USA), Prosigna Breast Cancer Prognostic Gene Signature Assay (PAM50; NanoString Technologies, Seattle, WA, USA), and MammaPrint (Agendia, Amsterdam, the Netherlands), with the goal to categorize patients based on their potential benefit from continued endocrine therapy or chemotherapy [ ].

In addition to the abovementioned therapeutic approaches, recent years have seen a prominent reemergence of immunotherapy as biological therapeutics, the idea where the patient's immune system is used to fight cancer cells [ ]. As of 2019, two immunotherapies have been approved to treat breast cancer treatment. The first is atezolizumab (Tecentriq) along with protein-bound paclitaxel (Abraxane), which is approved for locally advanced inoperable and metastatic TNBC that tested positive for the PD-L1 protein. Another approved candidate is pembrolizumab (Keytruda) for metastatic cancers that are microsatellite instability high or have DNA mismatch repair deficiency. These treatments are likely to work in patients with higher levels of PD-L1 or gene mutations but with considerable side effects. Nonetheless, there are more than 250 clinical trials underway extensively exploring immunotherapy for breast cancer treatment. Especially given the lack of efficient treatment option of TNBCs, there has been a constant need to develop novel drugs with much better efficacy than the existing ones offered for breast cancer therapy.

Drug repurposing

Drug repositioning, also referred to as drug repurposing or drug reprofiling, is the process of uncovering new indications of the approved or failed/abandoned compounds for use in a different disease [ ]. This approach benefits from the fact that such compounds have already undergone extensive rigor of elaborate phases of new drug discovery that often includes detailed information on their safety, efficacy, formulation, dose, and potential toxicity [ ] and in many instances, Phase I clinical trials. Fundamentally, drug repositioning is being made feasible because drugs perturb a multitude of biological processes that are common to many different diseases. Few of the prominent and obvious advantages of drug repositioning are a significant reduction in the cost and development time as their safety in humans is usually well established [ ]. Advances in genomics, proteomics, transcriptomics, and metabolomics have provided tremendous insights into the molecular and metabolic alterations that manifest in cancers. The fundamentals of drug repurposing through the integration of systems biology and bioinformatics depend on basic concepts, i.e., activity-based and in silico drug discovery [ ]. The former approach relies on utilizing experimental approaches to evaluate the anticancer activity directly. Drug candidates, which are structural similar, are likely to share biological activity and indications [ ]. Likewise, if the same metabolic pathway is affected in the two different conditions, then the drug candidates targeting the specific pathway can be utilized as therapeutics for both diseases despite their structural dissimilarity [ ]. The tendencies of the drugs with a strong side effect in certain disease can be explored further to see if these “off-target” effects for one disease could be relevant and novel for the treatment in some other disease [ , ].

In silico drug repositioning offers a new paradigm by integrating the wide range of high-throughput biological data for the discovery of novel indications for the existing drugs. Big data emerging from molecular interaction studies such as genome-wide association studies (GWAS), together with text-based searches using online Mendelian inheritance in man and PubMed databases can be utilized to perform systematic and coordinated bioinformatics analysis for repositioning studies. For example, researchers analyzed GWAS data together with proteomics and metabolomics and identified 992 proteins as potential antidiabetic targets, for which nine drugs were repositioned [ , ]. A recent study showcased a new approach, “Drug Repurposing from Control System theory,” which provides a comprehensive framework using control theory paradigm for drug repurposing that considers various limitations in the previous databases such as variation in gene of interest copy numbers, mutations, and lack of reference for normal range of gene expression in different diseases and generates a disease-specific mathematical models [ ].

Success stories of drug repurposing in breast cancer

Nobel laureate pharmacologist Sir James Black (1988) has stated that “the most fruitful basis for the discovery of a new drug is to start with an old drug.” The drug repurposing efforts echo this wisdom and attempt to utilize the unexplored therapeutic potential of the existing drugs. However, since usually the information about mechanism of action of these drugs is limited and narrow in addressing the question around the disease of intended use, most of the success stories of repositioned drugs are serendipitous to date. Often they were discovered during later stages of clinical trials as unexpected yet beneficial findings. Even though the drugs have established bioavailability and safety information, they cannot be extrapolated for new diseases due to unknown or complex mechanism of drug actions [ , ]. This scenario is rapidly changing as with the ever-growing knowledge emerging from bioinformatics approaches, more rational and systematic pipelines are generated/being generating to narrow down the pharmacologically relevant biomolecules for repurposing efforts. In this section, we have expanded on the stories of the drugs that have been successfully repositioned for each clinical subtype of breast cancer. While the term drug repurposing is often used for drugs that are now being used for diseases other than their original intended use, in this section, we also discuss oncology drugs that were originally approved for other cancer types besides breast cancer. For example, some of the repurposing candidates for TNBCs that are either in the preclinical or clinical trials stages were previously approved for other cancers. Finally, in addition to these success stories, we have elaborated on the potential drug candidates for repurposing, which have shown promises in the animal studies or are part of ongoing clinical trials in Section 6.4 . The approved repositioned drugs for breast cancer are listed in Table 6.1 , grouped according to subtypes.

Table 6.1

Advanced/FDA approved repositioned drugs in different breast cancer subtypes.

Breast cancer subtype	Drugs	Properties	Original use	Current status
Hormone receptor positive (estrogen receptor/progesterone receptor; ER/PR)	Tamoxifen	Estrogen receptor antagonist	Fertility drug (ovulation induction) Osteoporosis	FDA approved for breast cancer prevention and treatment
	Raloxifene	Estrogen receptor antagonist	Osteoporosis treatment in menopausal and postmenopausal women	FDA approved for breast cancer prevention
HER2 positive	Nelfinavir/Viracept	HIV protease inhibitor	HIV treatment	Preclinical study
	Propranolol	Beta-1 adrenergic receptors antagonist	Infantile hemangioma, hypertension, anxiety, cardiac arrhythmia, hyperthyroidism, infarction, thyrotoxicosis	Clinical trial
Triple-negative breast cancer and advanced metastatic breast cancer	Clofazimine/Lamprene	Antibacterial	Multibacillary leprosy treatment	Preclinical study
	Penfluridol	Synthetic nucleoside analog	Antipsychotic drug for schizophrenia treatment	Preclinical study
	Paclitaxel (PTX)/Taxol	Suppression of microtubule dynamics	Atrial restenosis, ovarian cancer	FDA approved for metastatic breast cancer combination therapy
	Gemcitabine	Cell division	Antiviral drug	FDA approved
	Goserelin	Luteinizing hormone–releasing hormone (LHRH) agonist	Prostate cancer, uterine fibroids, assisted reproduction	Phase II clinical trial standard neoadjuvant therapy for TNBC

Hormone receptor–positive breast cancer

Nearly 70% of the breast tumors are receptors positive, which are treated with antiestrogen therapy. These nuclear hormone receptors belong to large family of nuclear receptors that acts as transcription factors and are modulated by the steroid hormones estrogen and progesterone [ , ]. A series of epigenetic events contribute to ER signaling following stimulation of ER by estrogen. Therapeutics have effectively targeted ER signaling; for instance, tamoxifen antagonizes the binding of estrogen to the ER or downregulation of ER by fulvestrant (Faslodex) [ ].

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