Advances in Cancer Drug Targets: Volume 1 E-Book
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- Herausgeber: Bentham Science Publishers
- Kategorie: Fachliteratur
- Serie: Advances in Cancer Drug Targets
- Sprache: Englisch
Advances in Cancer Drug Targets is an e-book series that brings together recent expert reviews published on the subject with a focus on strategies for synthesizing and isolating organic compounds and elucidating the structure and nature of DNA. The reference work serves to give readers a brief yet comprehensive glance at current theory and practice behind employing chemical compounds for tackling tumor suppression, DNA site specific drug targeting and the inhibition of enzymes involved in growth control pathways. The reviews presented in this series are written by experts in pharmaceutical sciences and molecular biology. These reviews have been carefully selected to present development of new approaches to anti-cancer therapy and anti-cancer drug development. This e-book volume will be of special interest to molecular biologists and pharmaceutical scientists.
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Seitenzahl: 473
Veröffentlichungsjahr: 2013
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FOREWORD
Cancer drug therapy has evolved significantly in the last two decades. Progress in the synthesis and isolation of organic compounds as well as our understanding of the structure and nature of DNA have also contributed to advances in anti-cancer drug development. Contemporary biochemical strategies to combat cancers range from cytotoxic and DNA damaging mechanisms to regulating programmed cell death (apoptosis). This eBook is the first volume of the series Advances in Cancer Drug Targets and is a compilation of recent expert reviews published in Current Cancer Drug Targets on the subject with a focus on these strategies. The reference work serves to give readers a brief yet comprehensive overview of current theory and practice behind employing chemical compounds for tackling tumor suppression, DNA site specific drug targeting and the inhibition of enzymes involved in growth control pathways. The reviews, written by experts in pharmaceutical sciences and molecular biology, have been carefully selected and represent an attempt to collect and current research on anti-cancer drug development for interested researchers and pharmaceutical scientists. Advances in Cancer Drug Targets should also provide insights into development of new approaches to anti-cancer therapy. I hope that the articles contained in this volume will be greatly enjoyed by the readers.
I would like to thank Mr. Mahmood Alam, Mr. Taimur Khan, Ms. Nazia Kamran and Ms. Humaira Hashmi for their help and support.
LIST OF CONTRIBUTORS
The PIK3CA Gene as a Mutated Target for Cancer Therapy
Sarah Croessmann,Justin Cidado,John P. Gustin,David Cosgrove,Ben Ho Park1,2,*Abstract
The development of targeted therapies with true specificity for cancer relies upon exploiting differences between cancerous and normal cells. Genetic and genomic alterations including somatic mutations, translocations, and amplifications have served as recent examples of how such differences can be exploited as effective drug targets. Small molecule inhibitors and monoclonal antibodies directed against the protein products of these genetic anomalies have led to cancer therapies with high specificity and relatively low toxicity. Our group and others have demonstrated that somatic mutations in the PIK3CA gene occur at high frequency in breast and other cancers. Moreover, the majority of mutations occur at three hotspots, making these ideal targets for therapeutic development. Here we review the literature on PIK3CA mutations in cancer, as well as existing data on p110α inhibitors and inhibitors of downstream effectors for potential use as targeted cancer therapeutics.
INTRODUCTION
Insults to the genome are a hallmark of cancer and a driving force in carcinogenesis. These genomic alterations are an obvious difference between normal and cancerous cells, and provide an opportunity for exploitation as potential targets for therapeutics. Over the past decade, successful clinical trials of imatinib, gefitinib, erlotinib, and trastuzumab, which are specific for BCR-ABL translocations [1], epidermal growth factor receptor (EGFR) mutations [2, 3], and HER2/neu amplifications [4-6] respectively, have illustrated the ability to develop drugs that target genetic abnormalities in human malignancies. This has opened
the possibility for future streamlined therapies based on the genomic landscape of an individual’s cancer.
Phosphatidylinositol 3-kinases (PI3K)s are heterodimeric proteins consisting of a regulatory subunit (p85) and a catalytic component (p110), and there are several isoforms and classes of known PI3Ks. The p110α catalytic subunit of the Class I PI3Kα, encoded by the gene PIK3CA, is one of the most highly mutated oncogenes in human cancers. High mutational frequencies of PIK3CA have been reported in colorectal [7], breast [8] and liver cancers [9] while lower rates of mutation have been described in many other human malignancies including ovarian [10, 11], lung [7, 9], gastric [7, 9, 12, 13], and brain cancers [7, 9, 14-21]. In breast cancer, PIK3CA has a reported overall mutational rate of 25%, with more than 80% being attributed to “hot spot” regions within exon 9 of the helical domain and exon 20 of the catalytic domain [8]. These three mutations, E542K and E545K in exon 9 and H1047R in exon 20 lead to increased PI3K catalytic activity. This increased activity results in cellular transformation through growth factor- and anchorage-independent cellular proliferation [22-24]. Studying the effects of these mutations in colorectal cells [25-27], breast epithelial cells [28, 29], and chicken embryo fibroblasts [30, 31] have illustrated a direct connection between these mutations and carcinogenesis. Through crystallographic and biochemical methods, it has been determined that the probable oncogenic mechanism of the E545K mutation is the disruption of an inhibitory charge-charge interaction between p110α and the N-terminal SH2 domain of the p85 regulatory subunit [32] (Fig. 1). It has been previously proposed that the oncogenic mechanism of the E542K mutation is similar to E545K, exhibiting a change in the interaction of p110α with the p85 regulatory subunit. The proposed oncogenic mechanism of the H1047R mutation differs from the exon 9 mutations. The H1047R mutation increases the binding affinity of p110α for the negatively charged phosphatidylinositol substrate leading to increased activity and transforming potential [33]. Furthermore, aberrant PI3K signaling has also been linked to resistance of cells in preclinical models to a number of targeted and cytotoxic cancer therapies, including trastuzumab and paclitaxel resistance in human breast epithelial cells harboring PIK3CA mutations [28, 34]. Clinically, the presence of PIK3CA mutations has been linked to both favorable [35, 36] and unfavorable [37, 38] patient prognosis, and it has also been reported that exon 9 mutations have a less favorable prognosis than exon 20 mutations in breast cancer [39]. The reasons for these conflicting data are not clear, but likely reflect limited sample sizes and difference in treatment regimens between the various studies.
Figure 1)A representation of the Domains of the PI3K Subunits p110α and p85α. The p110α catalytic subunit has 5 domains including adaptor-binding domain (ABD), the Ras-binding domain (RBD), a calcium binding domain (C2), a helical domain and a kinase domain. The p85α regulatory subunit contains 5 domains as well, which include a Src homology 3 domain (SH3), a GTPase activating protein domain (GAP), an N-terminal Src homology 2 domain (nSH2), an inter- Src homology 2 domain (iSH2), and a C-terminal Src homology 2 domain (cSH2). The exon 9 hotspot mutations, E542K and E545K, occur in the helical domain of the catalytic subunit p110α, and the charge reversal caused by these mutations inhibits electrostatic interactions between those amino acids on the p110α helical domain and R340 and K379 on the nSH2 domain of p85α. The exon 20 hotspot mutation, H1047R, is in the kinase domain of p110α, and this mutation has been proposed to form a hydrogen bond with L956 of p110α, which in turn leads to catalytic activity of p110α.
TARGETING PIK3CA MUTATIONS
With the recent success of biologics and small molecular inhibitors for anti-cancer therapy, the identification and validation of additional therapeutic targets is of great importance and interest. PIK3CA somatic mutations would be ideal for targeting due to their high rate of occurrence and the fact that 80% to 90% of these mutations are in one of the three previously discussed hotspots. Below, we review several classes of targeted compounds that may have clinical utility for the treatment of cancers harboring PIK3CA mutations.
PI3K Inhibitors
The most direct method of targeting cancers that have PIK3CA mutations would be to develop inhibitors that have high specificity for mutant p110α but not its wild type counterpart. The ability to create relatively mutation-specific small molecule inhibitors is exemplified by erlotinib and gefitinib, which were initially developed as EGFR inhibitors but were found to be most effective in patients whose tumors contained specific EGFR mutations [40, 41]. This finding is attributed to oncogene addiction [40], which is the phenomenon whereby cancer cells become dependent on particular alterations for survival as well as preservation of the malignant state. Thus, specific genetic changes within cancer cells, such as the PIK3CA hotspot mutations, result in increased growth signals from aberrantly activated pathways, and therefore removal of these signals leads to decreased cellular growth and apoptosis [42]. Recent structural data demonstrate that rational design of mutation specific inhibitors is feasible [43], and therefore the emergence of targeted mutant PIK3CA therapies is likely to be imminent.
Prior to the discovery of somatic PIK3CA mutations in human cancers, the PI3K enzyme was already recognized as being an important molecule in mediating carcinogenesis. As such, inhibitors of PI3K were developed with the hope that a therapeutic window could be achieved. The earliest and best characterized PI3K inhibitors are wortmannin and LY294002. Both of these compounds have been shown to be effective anti-tumor agents in in vitro cell culture models, as well as in in vivo animal models [44-46]. LY294002 has been shown to inhibit both in vitro PI3K activity and phosphorylation of downstream effectors of PIK3CA in breast epithelial [28] and colorectal cancer cells [27]. However, due to their poor pharmacological properties and marked cytotoxicity, LY294002 and wortmannin do not have clinical utility as reviewed by Workman [47]. Additionally, they are not ideal for specifically targeting PIK3CA mutants because they can inhibit other kinases of the PI-3 kinase-like kinase (PIKK) family, and several other kinases such as the mammalian target of rapamycin (mTOR) [48-52]. Despite having limited preclinical studies due to poor solubility, instability and high toxicity, both the structures of LY294002 and wortmannin have served as templates for derivatives and prodrugs with better pharmacological properties [53, 54]. The prodrug, SF-1126, is a vasculature-targeting Arg-Gly-Asp peptide conjugated to LY294002 that exhibits increased stability and tolerance in murine models [55]. Similarly, wortmannin has served as an analog template for a pan-PI3K inhibitor, PX-866, which demonstrated increased cell permeability and a prolonged serum half-life [56]. Recently, a number of groups have reported developing p110α selective inhibitors [57-63], and some have demonstrated efficacy in vitro and in vivo [57-59, 61, 62, 64]. The development of subsequent generations of PI3K pathway inhibitors and combined therapies have aided in circumventing the limitations of first generation inhibitors [65].
Class-specific and isoform-specific PI3K inhibitors are attractive target options, providing the opportunity for global inhibition of downstream components. It is important to note, however, that PI3K inhibitors have the potential for greater toxicity due to their importance for normal cellular processes. Class I PI3Ks inhibitors, such as GDC-0941[66], XL-147 [67], BKM120 [68], GSK1059615, CAL-101[69], and PX-866[70], are currently in clinical development. Despite significant homology between the different p110 catalytic subunits (α, β, δ, γ), recent structural data supports the potential for success of current Class I PI3K p110 isoform-specific inhibitors [43], with a particular interest in p110α specific inhibitors due to the possibility of oncogenic PIK3CA mutations being predictors of response [71]. BYL719, GDC-0032, and INK-1117, are three p110α-specific inhibitors currently in early clinical development [72]. Initial studies have identified other p110 isoform-specific inhibitors TGX-221[73], CAL-101, and AS-252424 [74] for p110β, p110δ, and p110γ, respectively. Isoform-specific inhibitors demonstrate the ability to target particular alterations in the PI3K pathway with theoretically less off target effects. In addition to isoform specific inhibitors, Class specific inhibitors in pre-clinical studies have shown the possibility of preferential responses to tumors harboring PIK3CA mutations. For example the novel Class I PI3K inhibitor, CH5132799, is particularly selective for cancer cells harboring PIK3CA mutations [75]. In addition, other PI3K isoforms may also prove to be attractive targets for breast cancer therapy. For example, studies have demonstrated that expression of PIK3CB in conjunction with HER2 amplification, can lead to a worse overall prognosis [76]. The future development of isoform specific PI3K inhibitors may allow for novel therapeutic development and targeting of breast cancers based upon the genetic alterations that drive the PI3K pathway.
Buttressed against these exciting developments, specific targeting of PIK3CA may be problematic, because as previously mentioned, PIK3CA is involved in a number of signaling pathways associated with normal cellular function, such as insulin signaling [63, 77]. This may result in PIK3CA inhibitors that are prohibitively cytotoxic, thus limiting their clinical benefit. To illustrate this point, some PIK3CA inhibitors have been shown to abrogate the effects of insulin in mice [63]. Similarly, PIK3CA deficient mice have recently been shown to have an increased rate of heart failure in response to cardiac stress [78]. Thus, the possibility of a significant side effect profile has led to the development of compounds designed to target downstream effectors within the PI3K pathway with the hope that this may be a more effective strategy to target cancers containing PIK3CA mutations.
AKT Inhibitors
AKT, also known as protein kinase B, is a serine threonine kinase directly downstream of PI3K, and due to its central role in signal transduction, the dysregulation of AKT is commonly associated with many different cancers [79]. More specifically, constitutive activation of AKT has been associated with PIK3CA mutations in several in vitro cell models [26-30]. Therefore, AKT inhibitors may prove to be useful in targeting cancers with PIK3CA mutations.
AKT was identified as an oncogene over two decades ago [80], and multiple AKT inhibitors have been developed and used successfully to inhibit AKT activation and cellular growth in in vitro and in vivo tumor models [81-108]. Unlike PI3K, development of isoform-specific AKT inhibitors has proven difficult due to the high degree of homology among the three AKT isoforms. Perifosine is the most studied AKT inhibitor, proving efficacious at inhibiting the growth of various cancer cell types [105]. As a single agent, Perifosine has not shown therapeutic benefit in several phase II trials, however, Perifosine may have some therapeutic potential when used in combination with radiation or other standard cytotoxic agents, as evidenced by in vitro studies [109-111]. Another AKT inhibitor, Miltefosine, has shown efficacy in clinical trials for the topical treatment of cutaneous lymphoma and breast cancer skin metastases [112-115]. API-2, another early AKT inhibitor [102], had shown some efficacy in early phase trials, but was abandoned due to excessive toxicity [116, 117]. These early AKT specific compounds aided in directing the investigation of more specific AKT inhibitors at lower doses than those used previously, thus potentially avoiding detrimental side effects. Recent strategies for developing AKT inhibitors have included ATP-competitive inhibitors, phosphotidylinositol analogs, and allosteric inhibitors. GSK690693 and A-443654, two pan-AKT ATP-competitive agents, have demonstrated anti-tumor activity in preclinical models and are currently in early Phase trials [118, 119]. Allosteric inhibitors, such as MK-2205, have demonstrated relatively high selectivity and shown marked suppression of breast cancer growth, and are currently in late Phase II clinical trials [120]. These compounds interact with the pleckstrin homology (PH) domain or hinge region, promoting an inactive form of the enzyme by preventing localization to the membrane or access to the PDK-1-dependent phosphorylation site.
Additional studies are needed to further elucidate the relationship between PIK3CA mutations and AKT as there are three distinct isoforms (AKT1, AKT2, and AKT3) and each may have different effects on tumor growth and/or cytotoxicity. To date, PIK3CA mutations have been most closely linked to AKT1 in in vitro cell models [26, 28-30], with a single study examining all three isoforms revealing that AKT1 may be most affected by PIK3CA mutations [27]. However, isoform specific functions have been delineated through various laboratory studies. For example, RNA interference (RNAi) mediated gene knockdown of AKT1 in breast cancer cell lines has been shown to increase cell motility [121], and AKT1 knockout mice are small in size and infertile [122]. In addition, AKT2 knockout mice develop diabetes mellitus [123], while AKT3 knockout mice exhibit abnormal brain development [124]. Although AKT isoforms are highly homologous, selective AKT1 and 2 inhibitors have been developed and have shown promise in vitro [97]. Further study of the relative effects of inhibiting different AKT isoforms in cancers harboring PIK3CA mutations will be required, as the potential for significant toxicities remains obstacle challenge for using AKT inhibitors as effective targeted therapies for these cancers.
mTOR Inhibitors
mTOR is a downstream effector of PIK3CA and is very important for many cellular processes, including cell proliferation [125] and angiogenesis [126]. The mTOR pathway has been shown to be activated by PIK3CA mutations in both chicken embryo fibroblasts [30] and colorectal cancer cells [26]. Therefore, blocking the mTOR pathway may prove to be an effective strategy for targeting aberrant growth signaling in cancers with PIK3CA mutations.
mTOR inhibitors are the most mature in terms of their development and clinical use of potential compounds targeting cancers harboring PIK3CA mutations. Rapamycin, the prototypical mTOR inhibitor, was initially developed in the early 1970’s as an antifungal agent [127] and was later FDA approved as an immunosuppressive therapy [128]. As seen with most first generation inhibitors, rapamycin exhibited undesirable pharmacological properties. More reliable rapamycin analogs, or “rapalogs”, were developed and have shown cytostatic activity in preclinical models and anti-tumor activity when used in combination with chemotherapies [71]. RAD001 (everolimus), CCI-779 (temsirolimus), and AP-23573 (deferolimus), are three rapalogs that have exhibited variable and moderate success. Previously, the best evidence of response was shown in the treatment of advanced renal cancers with temsirolimus [129]. More recently, the BOLERO-2 trial demonstrated that in metastatic breast cancer patients refractory to hormone therapies, the addition of everolimus to exemestane lead to improved progression free survival compared to women taking exemestane alone [130].
The proposed mechanism of action of rapamycin and its analogs is the formation of a complex with the FK506-binding protein (FKBP12). This complex can then bind the C-terminal region of mTOR, interfering with the kinase activity of the multimeric mTORC1 complex but not with mTORC2 [131]. Furthermore, identifying biomarkers that predict for response to mTOR inhibitors is paramount for the development of these agents, as response to mTOR inhibitors has been highly variable. Theoretically, PIK3CA mutations may lend themselves as predictive biomarkers for response to mTOR inhibitors. For example, rapamycin and its analogs prevent the transformation of chicken embryo fibroblasts expressing PIK3CA mutations [30], inhibit PIK3CA induced tumor growth in chicken embryos [31], and reduce the formation of abnormal human breast epithelial cell acini induced by mutant PIK3CA overexpression [28].
Despite the clinical potential of mTOR inhibitors, significant hurdles for their further development still exist. mTOR forms two complexes within cells, mTORC1 and mTORC2 [132]. mTORC1 is known to mediate a negative feedback loop with PI3K/AKT signaling, and therefore inhibiting mTOR pharmacologically causes a paradoxical upregulation of PI3K/AKT growth promoting signaling [133]. Additionally, mTORC2 directly phosphorylates AKT [134] but is only rarely inhibited by rapamycin and its analogs in a cell/tissue type dependent manner [135]. Despite the initial promise of the previously mentioned mTORC1 allosteric inhibitors, feedback activation of PI3K and AKT persists via mTORC2. This suggests a potential shift in the focus of compound development to ATP-competitive compounds that can inactivate both complexes and completely abrogate mTOR signaling. PP242, its derivative INK128, as well as several other pan-mTOR inhibitors such as AZD-8055 and OSI-027, are ATP-competitive compounds in early phase clinical trials for solid malignancies including breast cancers [136, 137]. Other effective strategies for targeting this complex signaling pathway in the future may include combining current mTOR inhibitors with either newer PI3K/AKT inhibitors or more traditional therapies, such as chemotherapy and endocrine therapy. In addition, it is possible that the current development of new inhibitors capable of blocking mTORC2, or alternatively both mTORC1 and mTORC2, could provide a more effective therapeutic regimen.
Possibilities of Novel Dual Inhibition
Due to the genetic instability of most human cancers, it can be expected that any targeted therapy when used as a single agent will ultimately succumb to drug resistance. However, the development of targeted therapies with minimal side effects would hopefully enable the combinatorial use of multiple drugs with non-overlapping toxicities, to effectively treat and eradicate the disease. Recently, it was demonstrated that the combination of p110α and mTOR inhibitors could prevent the increase in AKT signaling caused by mTOR inhibition alone [138]. A single molecule, PI-103, was found to effectively inhibit both p110α and mTOR, and its efficacy has been shown in gliomas, ovarian cancer, and breast cancer in in vitro and in vivo models [138, 139]. This class of molecules, capable of inhibiting multiple targets within the PI3K pathway, may prove to be an effective strategy for targeting cancer cells containing PIK3CA mutations.
In addition, combination therapies with existing anti-neoplastic drugs are also being explored. For example, PIK3CA mutations have been positively correlated with increased expression of both estrogen receptor alpha (ERα) and HER2 in the NCI 60 panel of cancer cell lines [140] as well breast tumor samples [141]. Hormonal therapies and trastuzumab are currently used to target ERα and HER2 respectively. However, it has been shown that increased AKT signaling is associated with resistance to both of these therapies [142-145], and it is therefore possible that PIK3CA mutations may actually confer resistance to these drugs. Recently, a study demonstrated that estrogen deprivation in ER (+) breast tumors increased the apoptotic effects of the PI3K and dual-PI3K/mTOR inhibitors, BKM120 and BGT226 respectively. Increased drug efficacy was observed when used in combination with fulvestrant, a selective estrogen receptor down-regulator (SERD) [146]. Recently, correlations have been made between the presence of mutant PIK3CA and activation of the MAPK pathway [147, 148]. While the development of combination therapies is still in its infancy, recent studies suggest that dual inhibition of both the PI3K and MAPK pathways presents the best strategy for targeting cancer with PIK3CA mutations, a testable hypothesis currently the focus of clinical trials.
CONCLUSIONS
Due to their high frequency in many cancers, PIK3CA mutations are a prime candidate for targeted therapeutics. However given the fact that these mutations have only recently been accurately characterized, much work lies ahead to fully elucidate their biological and clinical significance. The process of discovery for developing targeted PIK3CA therapies remains in its infancy. However, the wealth of potential targets along the PI3K pathway is certainly enticing from a developmental therapeutics viewpoint, and the opportunity exists to significantly impact cancer care with future success in this arena.
CONFLICT OF INTEREST
S.C., J.C., J.P.G. and D.P.C. declare no conflict of interests. B.H.P. is a member of the scientific advisory board of Horizon Discovery, LTD and receives royalties and payments for services provided and licensed reagents. B.H.P. is also a paid consultant for GlaxoSmithKline. The terms of these agreements are regulated by The Johns Hopkins University policies on conflicts of interest.
ACKNOWLEGMENTS
This work was supported by The Flight Attendant’s Medical Research Institute (FAMRI), NIH/NCI CA109274, the Summer Running Fund, The Susan G. Komen for the Cure Foundation, Mary Kay Ash Charitable Foundation and the Avon Foundation. J.P.G. is a past recipient of a Department of Defense Breast Cancer Research Program Predoctoral Fellowship Award W81XWH-06-1-0325. S.C., J.C. and D.P.C. were previously supported on NIH Institutional Training Grants CA067751, GM008752, CA09071 and an American Cancer Society Young Investigator Award (D.P.C.).
DISCLOSURE
The chapter submitted for the eBook Series entitled “Advances in Cancer Drug Targets, Volume 1” is an update of our article in Current Cancer Drug Targets, Volume 8, Issue 8, 2008, with additional text and references.
