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Targeted Drug Delivery for Sex Dependent Cancers

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Occurring cancer in any part of the human body such as lung, kidney, skin and etc. has a different incidence ratio between men and women. sex dependent cancers have seen just in male or female which is dependent to sex hormones and specific sex organs such as prostate cancer in male and Ovary and endometrial cancers in female, breast cancer is seen in both sex with 5% incidence in male. Despite of a self-explaining differentiation between the sex organs, since these organs functions are regulated by same hypothalamic gonadotropin-releasing hormone similarities in cell signaling and pathways via molecular interactions are highlighted for cancer studies and targeted therapy. Targeted drug delivery for sex dependent cancers has been studied for many years, but exploring similarities of sex-dependent cancers targeting could provide an opportunity for future targeted drug delivery of these cancers simultaneous effects analysis.

Breast Cancer:

Breast cancer (BC) is the most common cancer and cause of death among women worldwide during the past decades. To improve diagnosis, therapy and prevention of BC, molecular developments provide various techniques for scientist to study and differentiate BC cell lines as well as observe different phenotype of BC. They classified BC to three main subtypes: estrogen/progesterone receptor (ER) positive, epidermal growth factor receptor (HER2) positive, and triple negative breast cancer (TNBC).

Estrogen/progesterone receptor (ER) positive: In BC subtypes of ER+, the overexpression of estrogen receptors on breast cells and nucleus membranes cause the over uptake of estrogen [1]. Many studies showed that estrogen receptors could be targeted for anti-cancer delivery to breast cells. Some estrogen receptor targeted drugs now use in clinical therapy like tamoxifen from the family of SERMs (selective estrogen receptor modulators) which are competitive agonist of the estrogen receptor [2]. Arimidex, Fareston (Toremifene), Anastrozole, Exemestane, anastrozole, letrozole [3], [4],[5] Fulvestrant [6] are now in market.

Other estrogen receptor targeted drug is a family of aromatase Inhibitors (AI) that suspend the estrogen production. The third-generation aromatase inhibitors are classified into irreversible steroidal inhibitors and they have shown high potential to replace tamoxifen in postmenopausal women such as Exemestane, anastrozole, letrozole[2,4 ,5].

SERDs (selective estrogen receptor down-regulators) is another estrogen targeted that only drug with FDA approved is fulvestrant on the name of Faslodex used in metastatic hormone positive breast cancer [6].

HER2 positive: This breast cancer subtype is referred to overexpression of erbB2 (HER2) from the epidermal growth factor receptor family on breast cells membranes [7]. Anti HER2 agent has studied for targeted therapy of this subtype. Recombinant humanized monoclonal antibodies such as trastuzumab and pertuzumab are widely used for HER2 positive breast cancer and any other HER2 positive cancers [8][9][10]. Some monoclonal antibodies are under further clinical trials studies like ertumaxomab and margetuximab [11] .Her2 Vaccine is now under further studies [11].

Triple Negative breast cancer (TNBC): These subtype tumors do not express receptors for estrogen or progesterone and not overexpress the HER2 receptor. TNBC is a malignant cancer with the high rate of incidence in younger age and it grows faster with the high potential of metastasis in early stage while it is unlikely to be seen on annual mammogram [12]. Not only patients with TNBC almost show poor prognosis compare to other subtypes, but also during therapy they are at the higher risk of relapse, metastasis, and survival [13].

Since the clinical trial of some designed drug were not successful, no commercialized drug and therapy for this subtype still exists.

Endometrial Cancer:

Endometrial Cancer (EC) begins in the uterus cells of the endometrium layer. Mostly surgery including hysterectomy (removal of the uterus) and removal of ovaries and lymph nodes is the only way to cure the EC if biopsies show that cancer has not spread, no other treatment is needed.

According to clinic pathological characteristics, EC is classified to two subtype. Estrogen-dependent endometrioid and estrogen-independent non-endometrioid carcinoma. [14][15]. Estrogen-independent EC shows p53 and p16 mutations, overexpression of HER2 and E-cadherin loss [16]. Most of the diagnosed EC tumor are estrogen-dependent that express estrogen receptor and hormonal therapy with progestron is a primary line [17]. Since EC Type I express estrogen receptor the like ER+ BC mentioned previously, targeted therapies for EC are SERM, AI and GnRH inhibitors. Tamoxifen (as SERM) and anastrazole (as AI) commonly used. Anti-angiogenesis drugs are efficiently used for EC like Aflibercept, Abitrexate (Methotrexate) is an only trial drug for EC.

Prostate Cancer:

Prostate cancer is derived from the specific epithelial of secondary sex organs. Todays, the prostate cancer strategies of treatment is mostly based on suppressing testosterone level by anti-androgenic, gonadorelin agonist or antagonists [18]. Despite of the unknown active mutation in oncogenic pathways in prostate cancers subsets, some molecules express specifically in prostate epithelial cells which have been studied as therapeutic targets including; cell surface prostate-specific membrane antigen (PSMA), the secreted protease prostate-specific antigen (PSA), and the enzyme prostatic acid phosphatase (PAP).

  • PSMA targeting: PSMA is an integral cell surface membrane protein and specifically over-expressed in advanced prostate cancers. PSMA has been studied in phase II trial as a targeted therapy via monoclonal antibody (J591) conjugated with radio and chemical compounds [19].
  • PSA: The prostate-specific antigen (PSA) mostly use as an indicator for primary diagnosis of prostate cancer. Gonadorelin antagonists can suppress testosterone and PSA, by then Degarelix (Firmagon) is now using for treatment in prostate cancer patients. ARN-509 antiandrogen is only used for prostate cancer with high level of PSA indication.
  • PAP: Prostatic acid phosphatase (PAP) is an enzyme produced by prostate and the amount increased in prostate cancer cells. In clinical studies PAP mostly used as an antigen for anti-tumor vaccines [20].

Ovarian Cancer:

Ovarian Cancer is a 5th cause of cancer related death among women worldwide [21].Ovarian cancer has not yet been classified. It is poor diagnosed in stage I and in stage II,III,IV diagnosed by metastasis to other organs [22]. Surgery and aggressive chemotherapy are currently the only way to treat the ovarian cancer. Many studies on targeted therapy for ovarian cancer by nano-carriers are undergoing. Although, in market there is nano-carriers like liposome that carried chemotherapeutic agents like doxorubicin; DOXIL (Doxorubicin Hydrochloride Liposome), Evacet (Doxorubicin Hydrochloride Liposome) [23].

Novel Targeted therapy:

As previously has been mentioned, these cancers are mostly depended on sex hormones level, HER2 expression and other individual molecular marker indications. Almost all chemotherapy regiment have cytotoxic effect on non-cancer cells and caused the chemotherapy side effects. If these chemotherapy regiment could be conjugated with marker to specific targets of cancer cells the result would be cytotoxicity of drug just for cancer cells and no more side effects for healthy cells. This conjugation can be followed by protein based interactions like antigen- antibody mechanism or ligand-receptor affinity. Today novel therapeutical aims are trying to conjugate monoclonal antibodies with drugs which is called antibody-drug conjugated (ADC). Other novel targeted therapy is to conjugate the peptide or protein with drug (PDC). Both ADC and PCD are the subtype of protein drug conjugated approach. The result of covalent conjugation of drug with antibody or peptide is another novel strategy of prodrug in which after delivered to cells would be cleaved by an enzyme and release active drug [24]. For targeted drug delivery for any drugs two main subjects should be considered; Carrier and Targets:

  • Carriers:
  • Antibody:

In past decades, targeted drug delivery has been improved by development of antibodies against any identified targeted antigen. Not only antibodies can induce uptake of conjugated drug in targeted cells, but also they can enhance the role of complement-dependant cytotoxicity system to invade targeted cells. The potential of making almost any antigen as a target is an interesting properties of ADCs, however, just few of the human antibodies have shown a longer proper half-lives like IgG1, IgG2, and IgG4. Nearly 40 monoclonal antibodies (mAb) have been approved and develop not only for cancer but also for some autoimmune disease [25]. While antibodies have shown low loading capacity of drug, on molecule of antibodies are capable to conjugate with less than 3 molecules of drug, for improve ADCs efficacy drug should be highly potent.

As mentioned previously, HER2 is overexpressed in breast, prostate, ovarian and endometrial cancer that the anti-HER2 antibody can be used for targeted drug delivery. Antibody-drug conjugates (ADC) for HER2 positive is a conjugation of trastuzumab as an antibody and emtansine as cytotoxic compound and commercialized as TDM1. Other cytotoxic compound in conjugation with antibody is under further studies and clinical trial process like defucosylated trastuzumab [26],[27]. Lapatinib is commercialized drug from the family of Receptor tyrosine kinase inhibitors (RTKI) that target the intracellular binding site of HER and EGFR family [28].

In breast cancer antibodies of Anti-LIV1 mAb (hIgG1), Anti-GPNMB mAb (hIgG2), Anti-cripto mAb (hIgG1) in conjugation with drug Auristatin E and DM4 (maytansine) are now clinical Phase I. Anti-HER2 mAb (hIgG1) in conjugation with Emtansine-DM1 (maytansine) has been approved in early 2013 and used for metastatic breast cancer. Anti-TROP-2 mAb (mIgG1) in conjugation with SN-38 (irinotecan metabolite) is under further studies for triple negative breast cancer in Phase II clinical [29].

In prostate cancer Anti-PSMA mAb (hIgG1) in conjugation with Auristatin E (auristatin) is still on phase I clinical [30].

IgG1 ADC targets Folate receptor is in Phase 1 studies for ovarian cancer [31].

  • Protein/Peptide-drug conjugated (PDC):

Proteins are sequences of amino acids with 3D or 4D structures that have vital responsibility in all alive cells. Protein has been studied as a carrier for drug due to its stability, longer half-life, biodegradability and easy modification for carry drug with no effect on its desirable function [32]. Protein which are widely used as for drug delivery are Transferrin and Albumin [33], Zein [34], Elastin and Gelatine [35], Gliadin and Legumin [36].

The conjugation of albumin with methotrexate has been studied preclinical for many cancers but it had shown effect on just bone and prostate cancer [37]. Conjugation of transferrin with N-alkylisatin derivatives had shown 10 times more efficient on breast cancer tumor in vivo [38] and also conjugation with Artemisinin shown high toxicity for breast cancer in rat [39]. Gelatin conjugation with Gallic acid has been studied on prostate cancer [40].

Abraxane is an albumin conjugated with paclitaxel in phase I trial for metastatic breast cancer, prostate and ovarian cancer [41].

Peptide usually refers to a sequence of amino acids (up to 50) with just up to secondary structure [42]. Peptide ligand can be used for targeted receptors. However, peptides have short half-life and poor stability in serum as they can be degraded by protease, but peptides are smaller than antibodies and can easily penetrate the targeted cells and overcome biological barriers that the result would be the fast uptake of drug by targeted cells and also peptides have shown high drug loading potential [43].

Acyclic RGD4C as peptide c(Cys-Phe-Cys-Asp-Gly-Arg-Cys-Asp-Cys) in conjugation with doxorubicin has been shown higher antitumor activity on metastatic breast cancer in vivo than doxorubicin alone [44].

  • Targets:
  • Gonadotropin hormone receptor targeting:

The overexpression of luteinizing hormone releasing hormone (LHRH) receptors has been well reported on many cancer tumors specially breast, ovary, endometrial and prostate cancer [45],[46]. LHRH analog is widely used as a supplementary drug in order to bind to the LHRH receptor [47]. LHRH agonist induce downregulation of LHRH and suppress sex steroid hormone. While, LHRH antagonist block the LHRH receptors and suppress LHRH and sex steroid releasing immediately [48],[49]. Prostate cancer drug in market like Degarelix (Firmagon) (ANTAGONISTS), Lupron, Leuprolide Acetate, Zoladex (Goserelin Acetate) are LHRH analog [50].

LHRH and its analogue as a peptide with a sequence of 10 amino acids have been studied as a targeted drug carrier. AEZS-108 (formerly known as AN-152) is an LHRH agonist conjugation with doxorubin which is shown anti-cancer activity in phase II clinical trial of gynaecological cancers and a promising result for prostate cancer [51]. LHRH also has been studied for carry cisplatin encapsulated in dextran nano-particle to breast cancer cells [52]. Compound uptake via an interaction between LHRH and its receptor and then endocytosis by cell membrane. As normal cells with no overexpression of LHRH receptor could not uptake the drug, side effects of toxic drug significantly has been reduced36.

  • Growth factor targeting:

Growth factor refers to substances that stimulate cells proliferation and differentiation by binding to their receptors which is tyrosine kinase activate other cell pathways. Epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF) and their receptors are two class of growth factors that have been studied for targeted therapy:

  • Angiogenic pathway targeting:

In all cancers, tumor growth and metastasis depend on angiogenesis pathway which activated by vascular endothelial growth factors. VEGF family and their receptors (VEGFR) have been studied for inhibition of tomur growth and metastasis as their overexpression had been seen in most of the malignant cancers [53]. The stimulation of VEGF not only induces cells mitosis and abort apoptosis, but also caused the chemotherapy and radiotherapy resistance [54]. On the other hand, chemotherapy and radiotherapy could induce VEGF in tumor cells [55]. Hereby, today anti-VEGF drug have been added to chemotherapy regiment.

Ovarian cancer cell lines has shown overexpress of VEGFR as well as breast cancer cell line like MDA-MB-453, and MDA-MB-231,T-47D,and MCF7 [56]. Studies on triple negative breast cancer cell lines; MDA-MB-453; have shown that overexpression of VEGF protected cancer cells from apoptosis and improved cell mitosis and invasion [57]. Treatment of MDA-MB-453 and MDA-MB-231 with anti-sense oligonucleotide inhibition of VEGF has shown over 50% decrease in invasion by Martigel assay [58].

Targeting VEGF has been studied in Phase I and II clinical by designing monoclonal anti-body directly against VEGF that shown suppressing metastasis relapsed in patients with breast cancer [59][60][61]. Now, Bevacizumab (Avastin®) is a monoclonal anti-body that bind to VEGF that has studied in phase III trial for metastasis breast cancer. Successful result has been released in phase III trial studies E2100, AVADO, RIBBON-1 that have Bevacizumab as a supplement and chemotherapy regiment like paclitaxel, docetaxel, anthracycline-based as a first line treatment respectively [62][63][64].

  • Epidermal growth factor targeting:

Epidermal growth factor (EGF) is a factor that induce cell growth, proliferation, differentiation, and survival by binding to its receptor (EGFR) with tyrosine kinase activity. The EGFR from ErbB family (also known as HER) has shown overexpression in cell surface of many cancers, especially breast, prostate, and ovarian cancer. HER2 is a receptor with three domains of extracellular for ligand, transmembrane domain, and cytoplasmic domain with tyrosine kinase activity. The excess of HER2 on cell membrane and high tyrosine kinase activities induce the downstream signalling pathways like PI3K/AKT/mTOR as well as JAK/STAT pathways which suppress apoptosis and promote proliferation and survival. HER2 is overexpressed in 15-30% of invasive breast cancers [65][66][67]. Cetuximab (Erbitux) and panitumumab (Vectibix) are the two most advanced monoclonal anti-bodies targeting the extracellular domain of the receptor and inhibit ligand-receptor interaction and tyrosine kinase activity [68][69]. But an abnormal form of HER2 which has the lack of extracellular domain, known as P95, is still active but resistance to drug and antibodies that target the extracellular domain[70].

Antibody-drug conjugates (ADC) for HER2 positive is a conjugation of trastuzumab as an antibody and emtansine as cytotoxic compound and commercialized as TDM1. Other cytotoxic compound in conjugation with antibody is under further studies and clinical trial process like defucosylated trastuzumab26,[71]. Lapatinib is commercialized drug from the family of Receptor tyrosine kinase inhibitors (RTKI) that target the intracellular binding site of HER and EGFR family [72].

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