Elacridar as Adjuvant with Anticancer Drugs for Brain Tumors – Delivery, Safety, Efficacy and Toxicity

Elacridar (N-(4-(2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl)phenyl)-9,10-dihydro-5-methoxy- 9-oxo-4-acridine carboxamide) is a potent inhibitor of P-glycoprotein (PgP) and breast cancer resistance protein (BCRP). It has been investigated as modulator of efflux transporters, which are shown to be very active in various cancers. The PgP is over expressed on tumor cells and plays a key role cancer resistance to anti-cancer drugs, specifically chemotherapeutics that are thrown out of the tumor cells making them ineffective over time. Researchers are investigating whether inhibiting the PgP may shut down efflux pumps, particularly on cancer cells, thus facilitating entry of drug in cancer cells leading to selective damage to cancer cells rather than normal cells. Elacridar, one such PgP pump inhibitor holds promise as an adjuvant in cancer therapy since clinical trials are underway to test its safety and efficacy in humans. This short review will address very specifically the prospect of using elacridar as adjuvant with anticancer drugs to brain tumors. Since Blood Brain Barrier (BBB) and Brain Tumor Barrier (BTB) pose hurdles to anticancer drug delivery and their reverse transport possibly due to efflux transport proteins on BTB. This review elucidates ongoing research on elacridar delivery across BBB/BTB, and the drug’s safety, efficacy and toxicity. We further seek to present evidence that PgP modulators along with BTB permeabilizing agents such as potassium channel activators can be clinically developed as adjuvants with anticancer drugs.

Introduction

The Central Brain Tumor Registry (USA) has estimated global incidence of primary brain tumors to be about 256,213 in 2012, which increased to 26,070 in 2017. Furthermore, the incidence of secondary (metastatic) brain tumors will be nearly 10-fold higher than the primary brain tumors. Majority of brain tumor patients have very short life expectancy (1 year) even after receiving brain radiation and/ or surgical resection [1]. Glioma, specifically glioblastoma multiforme (GBM) is a deadly form of brain tumor and its management is extremely difficult because of heterogeneity, chemo resistance followed by inadequate delivery of anticancer drugs due to P-glycoprotein (PgP) transport pumps expression on tumor cells as well as in blood brain tumor barrier (BTB). BBB is a physical and biological barrier consisting of endothelial cells (ECs), tight junction proteins (TJp) connecting the ECs, glial, pericytes, and astrocytic foot processes allows essential nutrients, such as glucose and amino acids through receptor mediated endocytosis to maintain vital brain functions. The nutrients and most anticancer drugs (except lipohilic drug entities) that are generally water soluble (hydrophilic) require carrier-mediated transport, receptor-mediated transcytosis and absorptive-mediated transcytosis to enter the brain cells (Figure 1). Studies have shown that BBB obstructs delivery of over 98% of CNS drugs [2]. Hence, various methods are employed to get around the physiological barrier posed by the blood-brain tumor barrier (BTB), including inhibiting PgP proteins.

BBB/BTB and Drug Delivery

Most anti-cancer drugs generally fail to cross the BTB in sufficient quantities. The invading glioma cells in the tumor edges are ideal targets for anti-cancer agents due to the presence of unique gene/protein expression pattern [3]. Several promising anticancer drugs are effective against cancers outside the brain but fail against brain tumors in clinical trials, in part due to poor BTB penetration. For instance, Gleevec (Novartis, USA) is ineffective against brain tumors since it hardly crosses BTB, but has demonstrated efficacy in patients with chronic myelogenous leukemia and gastrointestinal stromal tumor [4]. Similarly, invading edges of brain tumor are not clearly detected by imaging agents as the agents do not penetrate intact BTB easily [5,6]. In order to develop methods for increasing delivery of new wave of targeted drug entities referred as nanomedicines to brain tumor, we need to have precise understanding of the basics of BBB and BTB biology and their permeability and efflux regulation

Glioma treatment

Conventional diagnosis and treatment are not successful in reducing glioma patient mortality. Further, low penetration of anticancer drugs across BTB makes the treatment very difficult. Complete excision of diffused gliomas is nearly impossible partly due to low detection by CT and MRI as the imaging agents do not fully penetrate the intact BBB at the tumor edges. In order to address this issue, we biochemically modulated BTB to increase permeability to drug and imaging agents, selectively to brain tumors in experimental glioma models [5].

Elacridar- Research and Development

Elacridar development as a clinical drug candidate has been well reviewed elsewhere [7], which documents drug transporter families, including PgP and BCAR. There is extensive discussion on ADME, PK-PD and translational aspect in drug discovery and development of these classes of PgP inhibitors.

Many studies have shown that elacridar is a potent inhibitor of PgP and breast cancer resistance proteins (BCRP) [8,9] and have described elacridar as a multidrug resistance-reversal drug that restored sensitivity of multidrug-resistant tumors to doxorubicin. A recent animal study reported brain distribution and bioavailability of elacridar after different routes of administration [10]. It was shown with different routes of elacridar administration that the brain-to-plasma partition coefficient of elacridar increased as plasma exposure increased, suggesting saturation of efflux transporters at BBB. The role of P-gP and BCRP in limiting the distribution of substrate drugs across BBB has been examined using elacridar as a dual inhibitor of both P-gP and BCRP. Drugs such as morphine and amprenavir were shown to be at higher levels in brain after coadministration with Elacridar [11,12]. Furthermore, elacridar increased brain distribution of several tyrosine kinase inhibitors (TKIs) including imatinib, dasatinib, gefitinib, sorafenib, and sunitinib [13-19]. Studies in mice have shown that P-gP and BCRP at the BBB limits brain penetration of sunitinib and its active metabolite, however, oral administration of elacridar improved brain penetration of sunitinib [19,20].

Furthermore, preclinical studies have shown that paclitaxel penetration was improved by coadministration of elacridar or tariquidar in brain tumor [21]. These studies further advances the claim that elacridar can be clinically useful in delivering and retention of anticancer drugs across BTB for better control of brain tumors

Chronic administration of elacridar poses many hurdles, including formulation due to its unfavorable physicochemical properties. Elacridar is extremely lipophilic making it insoluble in water and poorly soluble in most other aqueous solvents [22]. Preclinical studies have shown the variability in plasma and tissue concentrations. Even clinical trials found inter-subject variability after oral dosing [23]. With respect to brain tumors, its availability in brain tumors and its ability to shut down PgP is the key to its development as adjuvant with anticancer drugs. In this regard, elacridar brain penetration in mice was dose-dependent and affected by the P-gP and BCRP at the BBB as shown by positron emission tomographic imaging [24,25]. Therefore, its versatile clinical candidacy as adjuvant in brain tumor treatment is hampered by its unpredictable adsorption and elimination as shown in both preclinical models and clinical applications. Furthermore, careful elucidation of elacridar BTB penetration mechanism and its distribution in brain tumors when coadministered with anticancer drugs, including monoclonal antibodies (MAbs) and nanomedicines is critical.

In addition, co-administration of elacridar with anticancer drugs that are substrates for P-gP and BCRP might improve its BTB penetration for better efficacy. As the brain tumor is heterogeneous with uneven BTB permeability [26] across the tumor spread (metastatic brain tumors), it may throw an uncertain pharmacokinetic challenge with uneven spread of target tumor cells. Nevertheless, safe and efficacious elacridar is what we need at the moment if we need to control brain tumor growth by targeting tumor cells that express BCRP and PgP. Major concern in glioma therapy is tumor resistance to chemotherapy, partly due to their insufficient delivery and lack of retention in tumor cells [27]. Major interest with this strategy will be the efficient use of targeted therapies such as Herceptin, TRKIs and emerging nanomedicines that have shown promise in peripheral cancers while failing in controlling brain tumors due to reasons discussed above. Added advantage of improved delivery and longer retention of anticancer therapies is the potential use of low doses and milder neuro/ peripheral toxicity

Hence, drug delivery strategies must involve understanding of these BBB/BTB constituents and their interaction with tumor cells, as well. The BTB around the tumor allow very little while mostly throwing out anticancer drugs by efflux mechanism, including small molecules and therapeutic monoclonal antibodies (MAbs) back to the circulation. Researchers are working on variety of carriers such as nanomedicines and nanospheres that might penetrate BTB. Such nanomedicines armed with targeted drugs are expected to supplement conventional chemotherapy and radiotherapy. Development of nanomedicines for treatment of cancer is defined by their penetration across BTB vasculature that surrounds the tumor. Further nanomedicines’ retention in tumor cells without being expelled by multi drug resistant P-glycoprotein (PgP) efflux system (Figure 2) determines their efficacy. Recent success in controlling cancer by targeting tumor and tumor blood vessel-specific marker(s) has renewed interest in development of more precise and less toxic anticancer drugs [28]. More research is required to investigate how to increase tumor-specific drug delivery, improve bioavailability of cytotoxic agents to neoplasms, and at the same time minimize toxicity to normal tissues. Due to advances in personalized therapy, more targeted drugs like cetuximab (Erbitux®), and therapeutic MAbs like Herceptin, ABX-EGF, EMD 720000 and h-R3 are shown to be effective in treating cancers outside of brain. However, they fail to control brain tumors because they fail to cross BTB in adequate quantity. These targeted anticancer drugs are ineffective to block epidermal growth factor receptors (EGFR), which are often amplified and mutated in human gliomas. Despite evidence of ‘leaky’ tumor centre, the capillaries surrounding the proliferating glioma as well as the brain tissue surrounding the tumor are nearly as impermeable as the BBB [29]. It is incorrect to assume that the disrupted BBB facilitates drug delivery to gliomas because diffuse tumor-cell invasion is a hallmark of even low-grade gliomas. Hence, understanding the biochemical regulation of the BBB in its normal and abnormal state (BTB) is of great importance as efforts continue to deliver therapeutic compounds to brain tumors.