Prostate cancer remains a major cause of cancer-related mortality. Genetic clues to the molecular pathways driving the most aggressive forms of prostate cancer have been limited. Genetic inactivation of PTEN through either gene deletion or point mutation is reasonably common in metastatic prostate cancer and the resulting activation of phosphoinostide 3-kinase, AKT and mTOR provides a major therapeutic opportunity in this disease as mTOR inhibitors, HSP90 inhibitors and PI3K inhibitors begin to enter clinical development.
Prostate cancer is the second leading cause of cancer deaths in men. It is not invariably lethal, however, and is a heterogeneous disease ranging from asymptomatic to a rapidly fatal systemic malignancy. In 2005, the American Cancer Society estimates that there will be 234 300 new cases of prostate cancer and that 29 528 men will die of this disease (Jemal et al., 2005). Prostate cancers are typically detected through screening based on measurement of the serum prostate specific antigen (PSA) followed by prostate biopsy. The treatment of cancers confined to the prostate gland typically involves radical prostatectomy, external beam radiotherapy or radiotherapy delivered by seed implants (brachytherapy). While many patients with localized disease require no additional treatment, a subgroup will relapse and develop distant metastatic disease. Relapsed patients or patients who present with metastatic disease are treated by withdrawal of androgenic hormones either through medical castration using GNRH agonists or by orchiectomy. While the majority of patients will respond to hormone ablation, responses eventually give way to progressive, hormone-refractory prostate cancer. Additional therapeutic interventions including chemotherapy have some benefit, but of limited duration.
Prostate cancer can be divided epidemiologically into rare hereditary and the vastly more common sporadic forms. Although candidate inherited prostate cancer susceptibility genes have been identified such as the ELAC2, RNASEL, MSR1, NSB1 and CHEK2 genes, the proportion of cases of hereditary prostate cancer attributable to germline mutations in these loci is small and only occasional mutations in these candidate genes have been identified in sporadic prostate cancer (Hsieh et al., 2001; Xu et al., 2001; Casey et al., 2002; Rennert et al., 2002; Rokman et al., 2002; Xu et al., 2002).
The extent of somatic genetic alterations in prostate cancer is not fully understood. Primary prostate tumors are surrounded by stroma and metastatic tumors are typically localized to the bone. These factors contribute to the difficulty in obtaining high-quality tumor-enriched DNA suitable for genetic analysis. Negative mutations studies thus must be interpreted with great caution. Among the best characterized somatic genetic events are amplification of c-MYC and the androgen receptor (AR), mutation of p53, hemizygous deletion at 8p21 thought to target NKX3.1 and loss or mutation of RB1 (reviewed in Sellers and Sawyers, 2002). In 1997, the tumor suppressor gene PTEN was cloned from the 10q23 region, a region frequently targeted by loss of heterozygosity (LOH) in advanced cancers (Li and Sun, 1997; Li et al., 1997; Steck et al., 1997). Inheritance of a mutated germ line allele of PTEN is linked to the development of the related hamartoma syndromes Cowden disease (CD) and Bannayana–Zonana syndrome (BZS) (Liaw et al., 1997; Lynch et al., 1997; Nelen et al., 1997; Marsh et al., 1997a). CD is associated with an increased incidence of breast and thyroid malignancies (Marsh et al., 1997b); thus, germline mutations or PTEN confer an increased risk of malignancy. As will be detailed further below, somatic inactivation of PTEN is common in a number of cancers including prostate cancer, and over the past 8 years it has become clear that the loss of PTEN and subsequent activation of Akt is a critical event in human prostate cancer, and presents a pathway for rationally targeted molecular therapeutics.
PTEN – a regulator of the phosphoinositide-3 kinase pathway
PTEN – a PIP3 phosphatase
The PTEN gene encodes a dual-specificity phosphatase active against protein substrates (Myers et al., 1997). Surprisingly, however, it has much better phosphatase activity against lipid substrates and in particular against the D3 phosphorylated position of phosphoinositide-3,4,5 trisphosphate (PIP3) (Maehama and Dixon, 1998). This lipid is the direct product of the phosphoinositide-3 kinase holoenzyme, suggesting that PTEN might act as a direct antagonist to the PI3K signaling pathway – a known critical oncogenic signaling pathway. Indeed, cells lacking an intact copy of PTEN harbor elevated levels of PIP3.
PI3K is a critical mediator of multiple signaling pathways. Simplistically, receptor tyrosine kinase growth factor receptors become activated and bind to the p85 regulatory subunit. This subunit binds to the catalytic subunit (p110) and activates PI3K. PI3K then phosphorylates the inositol ring of PI4P or PI4,5P2 at the D position to generate PI3,4P2 and PI3,4,5P3, which act as secondary messengers (Cantley and Neel, 1999).
From PIP3 to PI3K and AKT
Important downstream targets of PI3K and of PIP3 include the serine–threonine Akt kinase family (also known as PKB). PIP3, once generated in the plasma membrane, recruits Akt and PDK1 to the plasma membrane through an interaction between the phosphoinositide and the Akt or PDK1 pleckstrin homology domains (PH). Once recruited to the plasma membrane, Akt is phosphorylated and activated by PDK1 (Downward, 1998). Thus, PTEN null cells also harbor constitutively activated levels of Akt. For example, the prostate cancer cell lines PC3 and LNCaP harbor deletions and point mutation of PTEN, rendering each PTEN null. In these cells, basal levels of phosphorylated and hence active Akt exceed the levels of Akt seen in PTEN wild-type cells under conditions of serum stimulation.
Akt promotes both cell growth and cell survival by inactivating its downstream substrates including GSK3, BAD, FOXO and TSC2. Importantly, studies in Caenorhabditis elegans and Drosophilla melanogaster have linked activation of Akt to regulation of certain FOXO transcription factors and to the activation of mTOR and p70S6K. Thus, as one might predict in human cancer cells lacking PTEN substrates of Akt including GSK3, FOXO proteins and TSC2 are also constitutively phosphorylated.
Linking tumor suppression by PTEN to regulation of PI3K signaling
While PTEN has been implicated in regulating non-PI3K pathway functions such as p53, the accumulating evidence supports the notion that transformation resulting from the loss of PTEN is likely mediated through dysregulation of the PI3K pathway. For example, the germline mutant PTEN; G129E retains the ability to dephosphorylate lipid substrates, but selectively lacks the lipid phosphatase activity (Myers et al., 1998; Ramaswamy et al., 1999). This germline mutation is associated with the identical phenotype as seen with mutations that render PTEN null for both lipid and protein phosphatase activity. In keeping with the central role of PI3K signaling downstream of PTEN inactivation, prostate cancer cells and other cancer cell lines lacking PTEN remain dependent upon activation of the PI3K pathway for growth and survival. Reconstitution of PTEN to such cells either arrests cells in G1 or induces apoptosis. PTEN reconstitution also suppresses the growth of PTEN-null prostate cancer cell lines in soft-agar and in nude mice. These phenotypic reversions also require the PTEN lipid phosphatase activity (Myers et al., 1998; Ramaswamy et al., 1999). Moreover, antagonizing signaling through the PI3K pathway can also revert the transformed phenotype of PTEN null prostate cancer cells. In a variety of mammalian systems, inactivation of Akt alleles, restoration of Forkhead activity or inhibition of mTOR and p70S6K activities reverses many aspects of the transformed phenotype that results from the loss of PTEN (Nakamura et al., 2000; Aoki et al., 2001; Neshat et al., 2001; Podsypanina et al., 2001; Stiles et al., 2002). Finally, the requirement for continued PI3K signaling elicited by PTEN loss in cancer cell lines is in keeping with the genetic connections established between PI3K, AKT and PTEN in D. melanogaster and C. elegans.
Thus, loss of PTEN leads to a continued dependence of PTEN-null cells on PI3K pathway activation. This continued dependence provides a notable therapeutic opportunity.
Somatic mutation of PTEN or PI3K pathway genes in human prostate cancer
Inactivating mutations in PTEN
The discovery of somatic alterations in the PI3K pathway in prostate cancer began with observations of LOH in the region of 10q. This event occurs in CaP with high frequency (30–60%) (Gray et al., 1995; Komiya et al., 1996) and two distinct commonly LOH regions have been identified at 10q22–q24 and 10q25, respectively, implying the presence of putative tumor suppressor genes at these loci (Komiya et al., 1996).
As mentioned above, PTEN maps to the 10q23.3 locus and is likely the tumor suppressor gene targeted by this genetic event (Li and Sun, 1997; Li et al., 1997; Steck et al., 1997). Somatic alterations of PTEN are common in other primary tumors including gliomas (Liu et al., 1997; Rasheed et al., 1997; Wang et al., 1997), endometrial cancers (Risinger et al., 1997; Tashiro et al., 1997), thyroid carcinoma (Dahia et al., 1997) and melanoma (Guldberg et al., 1997; Tsao et al., 1998).
Interest in genetic alterations in PTEN in prostate cancer began with the observation that PC-3 and LNCaP cell lines (2 of the 3 commonly used prostate cell lines) harbor either a deletion (PC-3) or a point mutation in PTEN (LNCaP) (Li et al., 1997; Steck et al., 1997). Somatic PTEN alterations have been reported for both localized and metastatic prostate cancers. These genetic alterations include homozygous deletions, LOH, and inactivating missense and nonsense mutations. Point mutations in primary tumors were found in one of 40 primary tumors (Dong et al., 1998) and in five of 37 primary tumors (Gray et al., 1998), while homozygous deletions but not mutations were seen in eight of 60 tumors (Wang et al., 1998). Finally, Cairns et al reported LOH in 23 of 80 primary tumors with either deletion or mutation of the remaining allele in 10 of the 23 LOH+ tumors. Thus, it is reasonable to conclude that a substantial minority (∼15%) of primary tumors harbors PTEN mutations. This is of notable interest, as only a minority of primary tumors are associated with progression to lethal prostate cancer.
Somatic PTEN alterations appear more common in metastatic cancers. Suzuki et al. (1998) noted that 12 of 19 patients with metastatic disease had a mutation in PTEN in at least one metastatic site. Xenografts derived from metastatic foci have a high rate of PTEN loss and, specifically, homozygous deletion (Vlietstra et al., 1998). In keeping with these data, our group has assessed copy number alterations and LOH patterns in primary, hormone-sensitive lymph node metastatic prostate cancer and hormone-refractory metastatic prostate cancer, using high-density (100 K) single-nucleotide polymorphism arrays (Beroukhim R et al., unpublished data). As shown in Figure 1, biallelic loss is first seen in lymph node metastases and occurs in 50% of metastatic hormone-refractory prostate cancer. The analysis of larger numbers of primary tumors is required before we can determine whether a fraction of these tumors harbors deletions as well. Together, the bulk of the data suggests that the prevalence of PTEN mutation increases in the metastatic disease setting. Similarly, when studied by immunohistochemistry, loss of PTEN protein occurs in approximately 20% of localized prostate tumors. In this setting, PTEN loss is highly correlated with advanced stage and high Gleason grade (McMenamin et al., 1999). Thus, there may be a subfraction of primary tumors that lose PTEN and are hence destined to become metatstatic and hormone-independent.
Alterations in Akt in human prostate cancer
While amplification of the AKT1 or AKT2 genes has been noted in pancreatic ductal carcinomas (Cheng et al., 1996; Miwa et al., 1996; Ruggeri et al., 1998) and in ovarian and gastric cancer specimens (Staal, 1987; Cheng et al., 1992; Thompson et al., 1996), amplification of these loci has not been observed in prostate cancer. To date, activating point mutations have not been described in either AKT1, 2 or 3 in prostate cancer.
The activation of Akt has been studied in prostate cancer specimens using immunohistochemical means to detect phosphorylated Akt (pS473). In some studies, staining was detected in nearly all PIN and invasive prostate cancer samples (Sun et al., 2001; Van de Sande et al., 2005), while in another study the intensity of pS473 staining was positively correlated, with high preoperative serum levels of PSA (Liao et al., 2003) or was significantly greater, with higher Gleason grades 8–10 than PIN (Malik et al., 2002; Kreisberg et al., 2004). The relationship between IHC detection of Akt activation and PTEN mutation has not been established in prostate cancer.
Alterations in PI3K in human prostate cancer
Amplification (Shayesteh et al., 1999) and mutation (Samuels et al., 2004) of the gene encoding the catalytic subunit of the type 1 PI3K alpha subunit (PIK3CA) have been described as frequent somatic events in ovarian cancer, in breast cancer, hepatocellular carcinoma and glioblastoma among many cancer types. (Bachman et al., 2004; Broderick et al., 2004; Campbell et al., 2004). In prostate cancer, however, neither amplification nor mutation has been reported to date.
Alterations in IGFI in human prostate cancer
An association between plasma levels of IGF-1 and the risk of death from prostate cancer has been observed in prospective, population-based cohort studies (Chan et al., 1998; Wolk et al., 1998). Here, those men who are in the top quintile of IGF1 levels have a statistically significant increase in the risk of death from prostate cancer. More recent studies obtained in the so-called post-PSA era of prostate cancer diagnosis have failed to find these same associations. Thus, there remains a lack of clarity surrounding this finding.
Murine models of prostate cancer based on PI3K pathway activation
PTEN knockout mice
Conventional deletion of both alleles of Pten leads to developmental defects and death at embryonic days 6.5–9.5 days (Di Cristofano et al., 1998; Podsypanina et al., 1999). Pten heterozygous (+/−) mice develop prostatic intraepithelial neoplasia with nearly 100% penetrance, but these lesions apparently do not progress to macroinvasive cancers (Di Cristofano et al., 1998; Podsypanina et al., 1999). The viability of the Pten+/− mice is compromised as a result of lymphoproliferation and tumors of intestines, mammary, thyroid, endometrial and adrenal glands. Thus, it has been difficult to look at the resulting prostate phenotype in older aged mice.
Heterozygosity of Pten also cooperates with a number of engineered secondary events to enhance the phenotype. Heterozygous or homozygous loss of Cdkn2b (p27Kip1), Nkx3.1 and Ink4a/p19arf all exacerbate the PTEN prostatic phenotype. For example, Pten+/− mice, in the background of the Cdkn2b−/− genotype, develop prostate cancer within 3 months with 100% penetrance (Di Cristofano et al., 2001). PIN was observed in Pten+/−, Ink4a/p19arf+/− or −/− earlier than in Pten+/− mice alone; however, progression to invasive cancer was not observed (You et al., 2002). PIN was observed earlier in Pten+/−,Nkx3.1+/− than in Pten+/− mice alone and invasive cancers with lymph node metastases are found in Pten+/−,Nkx3.1+/−, Cdkn2b+/− mice (Abate-Shen et al., 2003; Gao et al., 2004). Finally, despite the convergence of PTEN and TSC2 on a common downstream signaling pathway (mTOR) reduction of Tsc2 cooperates to induce invasive prostate cancers in Pten+/− mice (Ma et al., 2005a).
LoxP-PTEN knockout mice
To determine the consequence of prostate-specific deletion of Pten, mice harboring floxed alleles of Pten (Lesche et al., 2002) have been generated and intercrossed with mice bearing a transgene directing the constitutive prostate-specific expression of Cre-recombinase (ARR2PB-Cre). In mice lacking both alleles of Pten, PIN develops with earlier onset than in Pten+/− mice and leads to invasive prostate cancer and ultimately to metastatic cancer (Trotman et al., 2003; Wang et al., 2003). Similarly, homozygous deletion of Pten achieved using a PSA promoter-driven Cre-recombinase leads to invasive prostate cancer with a 100% penetrance (Ma et al., 2005b) and similar pictures of progression were seen in mice bearing MMTV-Cre and Pten flox alleles (Backman et al., 2004).
These data strongly support the role of PTEN as a tumor suppressor, with particular relevance to prostate cancer initiation and progression.
Prostate-specific Akt transgenic mice
A transgenic line expressing a myristoylated and hence constitutively activated form of human Akt-1 was generated, in which the rat probasin promoter was used to restrict expression to the prostate (Majumder et al., 2003). In this model, activated AKT1 is spatially overexpressed in the ventral and lateral prostates, starting as early as postnatal day 2. The overexpression and activation of downstream molecules results in the development of dysplastic lesions with severe atypia, histopathological features consistent with PIN. AKT activation also led to changes in gene expression that are also known to occur in human prostate cancers. Notable among the upregulated transcripts was prostate stem cell antigen (PSCA), a gene that is expressed in prostate ductal tips during prostate development (Reiter et al., 1998). In human prostate cancers, PSCA is expressed in almost all cases of high-grade PIN and is overexpressed in approximately 40% of local and as many as 100% of bone metastatic prostate cancers (Gu et al., 2000).
The PIN phenotype does not progress to cancer, but 30–40% of older Akt-transgenic mice develop a protuberant abdomen as a result of a bladder outlet obstruction. In contrast to the results obtained with loss of function alleles of Pten, Tg-Akt1 did not develop invasive or metastatic prostate cancer. This important difference in phenotype may reflect the biologic differences between activating only Akt1 as opposed to inactivating PTEN, with the subsequent activation of PI3K and Akt. Alternatively, strain differences and hence germline genetic modifiers could, at least in part, account for some of these differences in the Akt1 transgenic mice maintained in the FVB background.
Genetic suppression of the PTEN phenotype in murine systems
The development of therapeutics for reversing treating of PTEN null tumors has been an area of intensive investigation. This results primarily from the array of drugable kinases that are suitable targets downstream of PTEN loss. To date, limited experiments have been carried out in mice to try and ascertain whether genetic deletion of any given pathway component (e.g. Akt or PI3K) is sufficient to suppress the PTEN phenotype. First, studies of teratoma formation suggest that Akt-1 is a major effector of the proliferation and tumor phenotype in PTEN homozygous (−/−) ES cells (Stiles et al., 2002). It has been more difficult to address the necessity of PI3K downstream of PTEN loss as mice lacking catalytic subunits of p110 are not viable; however, it has been possible to examine the requirement for the regulatory subunits of PI3K. Specifically, loss of the p85α and p85β subunits of PI3K in Pten+/− mice does not alter the PIN formation, but a fraction of the proliferating cells in PIN is reduced in Pten+/− p85β−/− mice (Luo et al., 2005a).
Akt, a regulator of mTOR and its role in prostate cancer
The mTOR pathway is an important component of the downstream signaling cascade that is dysregulated by loss of function mutations in PTEN. These connections between activated Akt and activation of mTOR, likely involve Akt-dependent inactivation of TSC2 or proceed through the Akt or PDK1-dependent activation of p70S6K. In either case, cells lacking PTEN or harboring activated alleles of Akt have high levels of mTOR activity and a resulting dysregulation of cell size, organ size and cell growth controls.
The mammalian target of rapamycin (mTOR) was identified after the discovery of its yeast homologs TOR1 and TOR2 (Brown et al., 1994; Chiu et al., 1994; Sabatini et al., 1994). mTOR is a member of the atypical protein kinase family and phosphorylates substrates critical for protein synthesis, including ribosomal subunit S6 kinase (S6K) and eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) (Schmelzle and Hall, 2000). Thus, the output of mTOR signaling is likely mediated through regulation of protein translation. How mTOR activation might lead to cellular transformation is still not completely clear. Downstream of mTOR broad alterations in protein translation might account for oncogenesis. Alternatively, specific critical proteins that are regulated through translation might be deregulated and may contribute to the required oncogenic signals. For example, it has also been proposed that dysregulation of the protein synthesis machinery through mTOR may generate cell-cycle progression signals that contribute to cancer (Ruggero and Pandolfi, 2003). Another potential target of mTOR is PP2A, which is downregulated by small T-antigen and is important for the transformation of human cells with SV40 T-antigens and Ras (Hahn et al., 2002). mTOR phosphorylates PP2A in vitro likely leading to downregulation of PP2A preventing the dephosphorylation of 4E-BP1 (Peterson et al., 1999). Thus, it is possible that PP2A is a critical target of mTOR-mediated signals.
In this vein, emerging data suggest that Hif1α stabilization may play an important role downstream in the induction of the neoplastic phenotype in vivo, and that mTOR inhibition, at least in part, reverts aspects of transformation through regulation of Hif1α levels (Hudson et al., 2002; Brugarolas et al., 2004; Majumder et al., 2004). Hif1α transcriptional targets are constitutively activated in the Akt-dependent prostatic intraepithelial neoplasia model, and this deregulation is completely mTOR dependent. Among the targets of Hif1α transcription are included nearly all the members of the glycolysis pathway from hexokinase to lactate dehydrogenase. An important implication is that the regulation of glycolysis and glucose uptake may likewise play an important role in the growth of such tumors.
With respect to Hif1α regulation, both Akt-dependent/mTOR-independent pathway and Akt dependent/mTOR-dependent pathways have been described (reviewed in Semenza, 2003; Abraham, 2004). Recent data suggest that hypoxia-induced activation of Hif1α requires mTOR activity (Zhong et al., 2000; Hudson et al., 2002), that insulin activates Hif1α through the Akt/mTOR-dependent pathway (Treins et al., 2002) and that in the setting of loss of TSC2, Hif1α protein and mRNA levels are elevated, leading to upregulated expression of Hif1α target genes (Brugarolas et al., 2003). Elevated Hif1α activity is, in this setting, reversed by mTOR inhibition (Brugarolas et al., 2003), but the mechanism leading to mTOR-dependent elevated Hif1α activity remains unclear.
Glucose uptake and in particular hexokinase activity can be ‘sensed’ or imaged in vivo using the radiotracer 18Fluorodeoxyglucose and positron emission tomography (18FDG-PET). Generally, 18FDG-PET uptake by tumors is thought to simply reflect upregulated metabolic activity; however, the regulation by mTOR suggests that genetic alteration of the pathway may specifically turn on glycolytic enzymes. Indeed, preclinical proof-of-concept experiments have shown that 18FDG-PET uptake can be blocked by two doses of the rapamycin derivative RAD001 (Figure 2) (McSheehy et al., 2005). This provides the opportunity to use 18FDG-PET as an in vivo pharmacodynamic marker for mTOR inhibitors.
Strategies for blocking the PI3K/Akt/mTOR pathway in prostate cancer
The frequent occurrence of inactivating mutations in the PTEN tumor suppressor in hormone-refractory prostate cancer has provided one of the few genetically defined in-roads to cancer therapeutics in prostate cancer. The PI3K pathway presents a number of attractive kinase targets for small molecule development that will be discussed below. Furthest along in clinical development are the inhibitors of mTOR, all of which are derivatives of rapamycin.
IGF1R has long been known as a critical survival and proliferation signal transducer. While genetic alterations in cancer have not yet been observed, murine fibroblasts that lack IGFIR are resistant to the transforming activities of a number of oncogenes including SV40 large-T antigen (Coppola et al., 1994). These latter data suggest that IGFIR is required for transformation and thus might be a suitable drug target. The IGFI/IGFIR axis is clearly important in human prostate development and in the development of prostate cancer. Indeed, constitutive secretion of IGFI itself in transgenic animals is sufficient to induce prostate cancer (DiGiovanni et al., 2000). Examination of IGFI−/− mice has also revealed that IGFI is required for the normal development of the murine prostate (Ruan et al., 1999).
IGFIR small-molecule inhibitors are in development and have reported activity against myeloma, small cell lung cancer and certain sarcomas; however, activity against prostate cancer has not been described to date (Garcia-Echeverria et al., 2004; Mitsiades et al., 2004; Scotlandi et al., 2005; Warshamana-Greene et al., 2005). It is also not clear whether such inhibitors would have preferential activity against PTEN-null cells or conversely whether loss of PTEN might render cells resistant to upstream IGFIR inhibition. Similarly, humanized selective antibodies directed against IGFIR are also in development, but whether such antibodies will have therapeutic efficacy remains to be seen (Burtrum et al., 2003; Maloney et al., 2003; Cohen et al., 2005).
There are ongoing efforts to develop kinase inhibitors against the catalytic subunits of PI3K. Early leads in this area include the commonly used laboratory tool compounds wortmannin and LY294002, which target the p110 catalytic unit of PI3K. These molecules have relatively broad specificity and short in vivo half-life and are poorly suited for clinical development. Second generation PI3K inhibitors, though not widely published appear to have much improved isoform specificity and also improved pharmacologic properties and activity in xenograft models (Ward et al., 2003; Workman, 2004). Again, however, whether there will be enhanced sensitivity in cells lacking PTEN or whether there is activity in prostate cancer models remains to be seen. These agents have not yet reached the clinic.
An alternative strategy for interrupting PI3K signaling is to block recruitment of the PI3K holoenzyme to receptor tyrosine kinases by disrupting the phosphotyrosine binding of the SH2-domain of the p85 subunit of PI3K. Here, peptidomimetics have been successfully used to block this association (Eaton et al., 1998), but will likely require significant optimization prior to in vivo administration.
Inhibition of Akt remains an attractive therapeutic approach to interdiction of the PI3K pathway. Despite serious efforts directed at building ATP-competitive kinase inhibitors, no selective small molecules have made it to the clinic. High potency inhibitors have been described (Thimmaiah et al., 2005; Luo et al., 2005b) and appear to have antitumor activity in xenografts models, although with some evidence of metabolic toxicities. In addition, a set of allosteric inhibitors that requires the PH domain of Akt for activity have been described (Barnett et al., 2005; Lindsley et al., 2005) and in vitro, induce apoptosis in the PTEN-null LNCaP prostate cell line. Finally, a number of ‘akt’ or pathway inhibitors have been described including calmodulin inhibitors (Kau et al., 2003), myo-inositol derivatives (Meuillet et al., 2004; Tabellini et al., 2004) and phosphatidylinositol ether analogs (Gills and Dennis, 2004) that inhibit the activation of Akt as measured by inhibition of Akt phosphorylation itself (as opposed to direct activation of Akt kinase activity). These latter agents might act either on Akt recruitment or on known or novel upstream activators of Akt. To date, there is no significant clinical experience with these agents in prostate cancer patients.
It appears that either events that lead to the activation of protein kinases, or kinases bearing activating mutations become particularly dependent on chaperone function for appropriate folding and activity. Notable in this regard is that phosphorylated and hence activated Akt likewise appears to require the function of the HSP90 chaperone for continued activity (Sato et al., 2000; Hostein et al., 2001; Basso et al., 2002; Solit et al., 2003; Gills and Dennis, 2004). Geldanamycin or its derivative 17-AAG are ansamycins that selectively inhibit HSP90 function by occupying the nucleotide binding site. The ansamycins appear to have anticancer activity and have prompted the development of new series of HSP90 inhibitors with improved pharmacologic properties and facile syntheses (reviewed in Chiosis et al., 2003; Cheung et al., 2005).
Recently, phase I data were reported for 17-AAG. Here, the dose-limiting toxicities were diarrhea and hepatoxicity. There were two patients with melanoma who had evidence for disease stabilization and no patients with prostate cancer were treated in this study (Banerji et al., 2005).
Rapamycin, first isolated from Streptomyces hygroscopicus, binds to FKBP12 (also known as FK506-binding protein) and induces binding to and inactivation of mTOR. Cell lines harboring inactivating mutations in PTEN are particularly sensitive to rapamycin or the derivative CCI-779 (Neshat et al., 2001). Similarly, chicken fibroblasts transformed by activating alleles of AKT or PI3K also have increased sensitivity to these agents (Aoki et al., 2001). In vivo, treating Pten+/− null mice with CCI-779 reduces the number of intestinal lesions (Podsypanina et al., 2001) and the treatment of Akt transgenic animals with RAD001 completely reverts the PIN phenotype to normal (Majumder et al., 2004). These experiments have encouraged the clinical development of mTOR inhibitors in the context of PTEN or PI3K pathway alterations. However, the mTOR-dependent regulation of Hif1α also raises the possibility that rapamycin or its derivatives might have a role as anti-angiogenic agents.
Current status of mTOR inhibitors in prostate cancer
Three derivatives of rapamycin CCI-779, RAD001 and AP 23573 (see Figure 3) either have completed or are completing phase I trials (Table 1). A phase II trial of CCI-779 was initiated in prostate cancer using intravenous weekly dosing. Toxicity may have resulted in the premature closure of this trial and no data have been reported in the published literature. A number of new phase II trials are underway, including a combination trial of Gefitinib and RAD001 in prostate cancer, as well as a Taxotere and RAD001 trial. Both of these trials will use 18FDG-PET imaging as a pharmacodynamic end point. It will likely be some time before we know whether mTOR inhibition will have therapeutic value in selected patients or in combination with second agents.
The genetic evidence strongly supports the role of PTEN mutation and hence AKT activation in metastatic or high-grade prostate cancers. Therapeutics for these aggressive forms of prostate cancer are severely lacking and agents targeting this pathway are likely to find a role in the management of prostate cancer. The major hurdles remain the discovery, optimization and clinical development of small molecule inhibitors for the major kinases dysregulated by PTEN loss, namely AKT and PI3K.
Abate-Shen C, Banach-Petrosky WA, Sun X, Economides KD, Desai N, Gregg JP, Borowsky AD, Cardiff RD and Shen MM . (2003). Cancer Res., 63, 3886–3890.
Abraham RT . (2004). Curr. Top. Microbiol. Immunol., 279, 299–319.
Aoki M, Blazek E and Vogt PK . (2001). Proc. Natl. Acad. Sci. USA, 98, 136–141.
Bachman KE, Argani P, Samuels Y, Silliman N, Ptak J, Szabo S, Konishi H, Karakas B, Blair BG, Lin C, Peters BA, Velculescu VE and Park BH . (2004). Cancer Biol. Ther., 3, 772–775.
Backman SA, Ghazarian D, So K, Sanchez O, Wagner KU, Hennighausen L, Suzuki A, Tsao MS, Chapman WB, Stambolic V and Mak TW . (2004). Proc. Natl. Acad. Sci. USA, 101, 1725–1730.
Banerji U, O'Donnell A, Scurr M, Pacey S, Stapleton S, Asad Y, Simmons L, Maloney A, Raynaud F, Campbell M, Walton M, Lakhani S, Kaye S, Workman P and Judson I . (2005). J. Clin. Oncol., 23, 4152–4161.
Barnett SF, Defeo-Jones D, Fu S, Hancock PJ, Haskell KM, Jones RE, Kahana JA, Kral AM, Leander K, Lee LL, Malinowski J, McAvoy EM, Nahas DD, Robinson RG and Huber HE . (2005). Biochem. J., 385, 399–408.
Basso AD, Solit DB, Munster PN and Rosen N . (2002). Oncogene, 21, 1159–1166.
Broderick DK, Di C, Parrett TJ, Samuels YR, Cummins JM, McLendon RE, Fults DW, Velculescu VE, Bigner DD and Yan H . (2004). Cancer Res., 64, 5048–5050.
Brown EJ, Albers MW, Shin TB, Ichikawa K, Keith CT, Lane WS and Schreiber SL . (1994). Nature, 369, 756–758.
Brugarolas J, Lei K, Hurley RL, Manning BD, Reiling JH, Hafen E, Witters LA, Ellisen LW and Kaelin Jr WG . (2004). Genes Dev., 18, 2893–2904.
Brugarolas JB, Vazquez F, Reddy A, Sellers WR and Kaelin Jr WG . (2003). Cancer Cell., 4, 147–158.
Burtrum D, Zhu Z, Lu D, Anderson DM, Prewett M, Pereira DS, Bassi R, Abdullah R, Hooper AT, Koo H, Jimenez X, Johnson D, Apblett R, Kussie P, Bohlen P, Witte L, Hicklin DJ and Ludwig DL . (2003). Cancer Res., 63, 8912–8921.
Campbell IG, Russell SE, Choong DY, Montgomery KG, Ciavarella ML, Hooi CS, Cristiano BE, Pearson RB and Phillips WA . (2004). Cancer Res., 64, 7678–7681.
Cantley LC and Neel BG . (1999). Proc. Natl. Acad. Sci. USA, 96, 4240–4245.
Casey G, Neville PJ, Plummer SJ, Xiang Y, Krumroy LM, Klein EA, Catalona WJ, Nupponen N, Carpten JD, Trent JM, Silverman RH and Witte JS . (2002). Nat. Genet., 32, 581–583.
Chan JM, Stampfer MJ, Giovannucci E, Gann PH, Ma J, Wilkinson P, Hennekens CH and Pollak M . (1998). Science, 279, 563–566.
Cheng JQ, Godwin AK, Bellacosa A, Taguchi T, Franke TF, Hamilton TC, Tsichlis PN and Testa JR . (1992). Proc. Natl. Acad. Sci. USA, 89, 9267–9271.
Cheng JQ, Ruggeri B, Klein WM, Sonoda G, Altomare DA, Watson DK and Testa JR . (1996). Proc. Natl. Acad. Sci. USA, 93, 3636–3641.
Cheung KM, Matthews TP, James K, Rowlands MG, Boxall KJ, Sharp SY, Maloney A, Roe SM, Prodromou C, Pearl LH, Aherne GW, McDonald E and Workman P . (2005). Bioorg. Med. Chem. Lett., 15, 3338–3343.
Chiosis G, Lucas B, Huezo H, Solit D, Basso A and Rosen N . (2003). Curr. Cancer Drug Targets, 3, 371–376.
Chiu MI, Katz H and Berlin V . (1994). Proc. Natl. Acad. Sci. USA, 91, 12574–12578.
Cohen BD, Baker DA, Soderstrom C, Tkalcevic G, Rossi AM, Miller PE, Tengowski MW, Wang F, Gualberto A, Beebe JS and Moyer JD . (2005). Clin. Cancer Res., 11, 2063–2073.
Coppola D, Ferber A, Miura M, Sell C, D'Ambrosio C, Rubin R and Baserga R . (1994). Mol. Cell Biol., 14, 4588–4595.
Dahia PL, Marsh DJ, Zheng Z, Zedenius J, Komminoth P, Frisk T, Wallin G, Parsons R, Longy M, Larsson C and Eng C . (1997). Cancer Res., 57, 4710–4713.
Di Cristofano A, De Acetis M, Koff A, Cordon-Cardo C and Pandolfi PP . (2001). Nat. Genet., 27, 222–224.
Di Cristofano A, Pesce B, Cordon-Cardo C and Pandolfi PP . (1998). Nat. Genet., 19, 348–355.
DiGiovanni J, Kiguchi K, Frijhoff A, Wilker E, Bol DK, Beltran L, Moats S, Ramirez A, Jorcano J and Conti C . (2000). Proc. Natl. Acad. Sci. USA, 97, 3455–3460.
Dong JT, Sipe TW, Hyytinen ER, Li CL, Heise C, McClintock DE, Grant CD, Chung LW and Frierson Jr HF . (1998). Oncogene, 17, 1979–1982.
Downward J . (1998). Curr. Opin. Cell Biol., 10, 262–267.
Eaton SR, Cody WL, Doherty AM, Holland DR, Panek RL, Lu GH, Dahring TK and Rose DR . (1998). J. Med. Chem., 41, 4329–4342.
Gao H, Ouyang X, Banach-Petrosky W, Borowsky AD, Lin Y, Kim M, Lee H, Shih WJ, Cardiff RD, Shen MM and Abate-Shen C . (2004). Proc. Natl. Acad. Sci. USA, 101, 17204–17209.
Garcia-Echeverria C, Pearson MA, Marti A, Meyer T, Mestan J, Zimmermann J, Gao J, Brueggen J, Capraro HG, Cozens R, Evans DB, Fabbro D, Furet P, Porta DG, Liebetanz J, Martiny-Baron G, Ruetz S and Hofmann F . (2004). Cancer Cell, 5, 231–239.
Garraway LA, Widlund HR, Rubin MA, Getz G, Berger AJ, Ramaswamy S, Beroukhim R, Milner DA, Granter SR, Du J, Lee C, Wagner SN, Li C, Golub TR, Rimm DL, Meyerson ML, Fisher DE and Sellers WR . (2005). Nature, 436, 117–122.
Gills JJ and Dennis PA . (2004). Expert Opin. Invest. Drugs, 13, 787–797.
Gray IC, Phillips SM, Lee SJ, Neoptolemos JP, Weissenbach J and Spurr NK . (1995). Cancer Res., 55, 4800–4803.
Gray IC, Stewart LM, Phillips SM, Hamilton JA, Gray NE, Watson GJ, Spurr NK and Snary D . (1998). Br. J. Cancer, 78, 1296–1300.
Gu Z, Thomas G, Yamashiro J, Shintaku IP, Dorey F, Raitano A, Witte ON, Said JW, Loda M and Reiter RE . (2000). Oncogene, 19, 1288–1296.
Guldberg P, thor Straten P, Birck A, Ahrenkiel V, Kirkin AF and Zeuthen J . (1997). Cancer Res., 57, 3660–3663.
Hahn WC, Dessain SK, Brooks MW, King JE, Elenbaas B, Sabatini DM, DeCaprio JA and Weinberg RA . (2002). Mol. Cell. Biol., 22, 2111–2123.
Hostein I, Robertson D, DiStefano F, Workman P and Clarke PA . (2001). Cancer Res., 61, 4003–4009.
Hsieh CL, Oakley-Girvan I, Balise RR, Halpern J, Gallagher RP, Wu AH, Kolonel LN, O'Brien LE, Lin IG, Van Den Berg DJ, Teh CZ, West DW and Whittemore AS . (2001). Am. J. Hum. Genet., 69, 148–158.
Hudson CC, Liu M, Chiang GG, Otterness DM, Loomis DC, Kaper F, Giaccia AJ and Abraham RT . (2002). Mol. Cell. Biol., 22, 7004–7014.
Jemal A, Murray T, Ward E, Samuels A, Tiwari RC, Ghafoor A, Feuer EJ and Thun MJ . (2005). CA Cancer J. Clin., 55, 10–30.
Kau TR, Schroeder F, Ramaswamy S, Wojciechowski CL, Zhao JJ, Roberts TM, Clardy J, Sellers WR and Silver PA . (2003). Cancer Cell, 4, 463–476.
Komiya A, Suzuki H, Ueda T, Yatani R, Emi M, Ito H and Shimazaki J . (1996). Genes Chromosome Cancer, 17, 245–253.
Kreisberg JI, Malik SN, Prihoda TJ, Bedolla RG, Troyer DA, Kreisberg S and Ghosh PM . (2004). Cancer Res., 64, 5232–5236.
Lesche R, Groszer M, Gao J, Wang Y, Messing A, Sun H, Liu X and Wu H . (2002). Genesis, 32, 148–149.
Li DM and Sun H . (1997). Cancer Res., 57, 2124–2129.
Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, Puc J, Miliaresis C, Rodgers L, McCombie R, Bigner SH, Giovanella BC, Ittmann M, Tycko B, Hibshoosh H, Wigler MH and Parsons R . (1997). Science, 275, 1943–1947.
Liao Y, Grobholz R, Abel U, Trojan L, Michel MS, Angel P and Mayer D . (2003). Int. J. Cancer, 107, 676–680.
Liaw D, Marsh DJ, Li J, Dahia PL, Wang SI, Zheng Z, Bose S, Call KM, Tsou HC, Peacocke M, Eng C and Parsons R . (1997). Nat. Genet., 16, 64–67.
Lindsley CW, Zhao Z, Leister WH, Robinson RG, Barnett SF, Defeo-Jones D, Jones RE, Hartman GD, Huff JR, Huber HE and Duggan ME . (2005). Bioorg. Med. Chem. Lett., 15, 761–764.
Liu W, James CD, Frederick L, Alderete BE and Jenkins RB . (1997). Cancer Res., 57, 5254–5257.
Luo J, Sobkiw CL, Logsdon NM, Watt JM, Signoretti S, O'Connell F, Shin E, Shim Y, Pao L, Neel BG, Depinho RA, Loda M and Cantley LC . (2005a). Proc. Natl. Acad. Sci. USA, 102, 10238–10243.
Luo Y, Shoemaker AR, Liu X, Woods KW, Thomas SA, de Jong R, Han EK, Li T, Stoll VS, Powlas JA, Oleksijew A, Mitten MJ, Shi Y, Guan R, McGonigal TP, Klinghofer V, Johnson EF, Leverson JD, Bouska JJ, Mamo M, Smith RA, Gramling-Evans EE, Zinker BA, Mika AK, Nguyen PT, Oltersdorf T, Rosenberg SH, Li Q and Giranda VL . (2005b). Mol. Cancer Ther., 4, 977–986.
Lynch ED, Ostermeyer EA, Lee MK, Arena JF, Ji H, Dann J, Swisshelm K, Suchard D, MacLeod PM, Kvinnsland S, Gjertsen BT, Heimdal K, Lubs H, Moller P and King MC . (1997). Am. J. Hum. Genet., 61, 1254–1260.
Ma L, Teruya-Feldstein J, Behrendt N, Chen Z, Noda T, Hino O, Cordon-Cardo C and Pandolfi PP . (2005a). Genes Dev, 19, 1779–1786.
Ma X, Ziel-van der Made AC, Autar B, van der Korput HA, Vermeij M, van Duijn P, Cleutjens KB, de Krijger R, Krimpenfort P, Berns A, van der Kwast TH and Trapman J . (2005b). Cancer Res., 65, 5730–5739.
Maehama T and Dixon JE . (1998). J. Biol. Chem., 273, 13375–13378.
Majumder PK, Febbo PG, Bikoff R, Berger R, Xue Q, McMahon LM, Manola J, Brugarolas J, McDonnell TJ, Golub TR, Loda M, Lane HA and Sellers WR . (2004). Nat. Med., 10, 594–601.
Majumder PK, Yeh JJ, George DJ, Febbo PG, Kum J, Xue Q, Bikoff R, Ma H, Kantoff PW, Golub TR, Loda M and Sellers WR . (2003). Proc. Natl. Acad. Sci. USA, 100, 7841–7846.
Malik SN, Brattain M, Ghosh PM, Troyer DA, Prihoda T, Bedolla R and Kreisberg JI . (2002). Clin. Cancer Res., 8, 1168–1171.
Maloney EK, McLaughlin JL, Dagdigian NE, Garrett LM, Connors KM, Zhou XM, Blattler WA, Chittenden T and Singh R . (2003). Cancer Res., 63, 5073–5083.
Marsh DJ, Dahia PL, Zheng Z, Liaw D, Parsons R, Gorlin RJ and Eng C . (1997a). Nat. Genet., 16, 333–334.
Marsh DJ, Zheng Z, Zedenius J, Kremer H, Padberg GW, Larsson C, Longy M and Eng C . (1997b). Cancer Res., 57, 500–503.
McMenamin ME, Soung P, Perera S, Kaplan I, Loda M and Sellers WR . (1999). Cancer Res., 59, 4291–4296.
McSheehy PM, Allegrini PR, Ametamey S, Becquet M, Honer M, Schubiger PA, Lane HA and O'Reilly T . (2005). Soc. Nuc. Med., Abstracts.
Meuillet EJ, Ihle N, Baker AF, Gard JM, Stamper C, Williams R, Coon A, Mahadevan D, George BL, Kirkpatrick L and Powis G . (2004). Oncol. Res., 14, 513–527.
Mitsiades CS, Mitsiades NS, McMullan CJ, Poulaki V, Shringarpure R, Akiyama M, Hideshima T, Chauhan D, Joseph M, Libermann TA, Garcia-Echeverria C, Pearson MA, Hofmann F, Anderson KC and Kung AL . (2004). Cancer Cell, 5, 221–230.
Miwa W, Yasuda J, Murakami Y, Yashima K, Sugano K, Sekine T, Kono A, Egawa S, Yamaguchi K, Hayashizaki Y and Sekiya T . (1996). Biochem. Biophys. Res. Commun., 225, 968–974.
Myers MP, Pass I, Batty IH, Van der Kaay J, Stolarov JP, Hemmings BA, Wigler MH, Downes CP and Tonks NK . (1998). Proc. Natl. Acad. Sci. USA, 95, 13513–13518.
Myers MP, Stolarov JP, Eng C, Li J, Wang SI, Wigler MH, Parsons R and Tonks NK . (1997). Proc. Natl. Acad. Sci. USA, 94, 9052–9057.
Nakamura N, Ramaswamy S, Vazquez F, Signoretti S, Loda M and Sellers W . (2000). Mol. Cell. Biol., 20, 8969–8982.
Nelen MR, van Staveren WC, Peeters EA, Hassel MB, Gorlin RJ, Hamm H, Lindboe CF, Fryns JP, Sijmons RH, Woods DG, Mariman EC, Padberg GW and Kremer H . (1997). Hum. Mol. Genet., 6, 1383–1387.
Neshat MS, Mellinghoff IK, Tran C, Stiles B, Thomas G, Petersen R, Frost P, Gibbons JJ, Wu H and Sawyers CL . (2001). Proc. Natl. Acad. Sci. USA, 98, 10314–10319.
Peterson RT, Desai BN, Hardwick JS and Schreiber SL . (1999). Proc. Natl. Acad. Sci. USA, 96, 4438–4442.
Podsypanina K, Ellenson LH, Nemes A, Gu J, Tamura M, Yamada KM, Cordon-Cardo C, Catoretti G, Fisher PE and Parsons R . (1999). Proc. Natl. Acad. Sci. USA, 96, 1563–1568.
Podsypanina K, Lee RT, Politis C, Hennessy I, Crane A, Puc J, Neshat M, Wang H, Yang L, Gibbons J, Frost P, Dreisbach V, Blenis J, Gaciong Z, Fisher P, Sawyers C, Hedrick-Ellenson L and Parsons R . (2001). Proc. Natl. Acad. Sci. USA, 98, 10320–10325.
Ramaswamy S, Nakamura N, Vazquez F, Batt DB, Perera S, Roberts TM and Sellers WR . (1999). Proc. Natl. Acad. Sci. USA, 96, 2110–2115.
Rasheed BK, Stenzel TT, McLendon RE, Parsons R, Friedman AH, Friedman HS, Bigner DD and Bigner SH . (1997). Cancer Res., 57, 4187–4190.
Reiter RE, Gu Z, Watabe T, Thomas G, Szigeti K, Davis E, Wahl M, Nisitani S, Yamashiro J, Le Beau MM, Loda M and Witte ON . (1998). Proc. Natl. Acad. Sci. USA, 95, 1735–1740.
Rennert H, Bercovich D, Hubert A, Abeliovich D, Rozovsky U, Bar-Shira A, Soloviov S, Schreiber L, Matzkin H, Rennert G, Kadouri L, Peretz T, Yaron Y and Orr-Urtreger A . (2002). Am. J. Hum. Genet., 71, 981–984.
Risinger JI, Hayes AK, Berchuck A and Barrett JC . (1997). Cancer Res., 57, 4736–4738.
Rokman A, Ikonen T, Seppala EH, Nupponen N, Autio V, Mononen N, Bailey-Wilson J, Trent J, Carpten J, Matikainen MP, Koivisto PA, Tammela TL, Kallioniemi OP and Schleutker J . (2002). Am. J. Hum. Genet., 70, 1299–1304.
Ruan W, Powell-Braxton L, Kopchick JJ and Kleinberg DL . (1999). Endocrinology, 140, 1984–1989.
Ruggeri BA, Huang L, Wood M, Cheng JQ and Testa JR . (1998). Mol. Carcinog., 21, 81–86.
Ruggero D and Pandolfi PP . (2003). Nat. Rev. Cancer, 3, 179–192.
Sabatini DM, Erdjument-Bromage H, Lui M, Tempst P and Snyder SH . (1994). Cell, 78, 35–43.
Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S, Yan H, Gazdar A, Powell SM, Riggins GJ, Willson JK, Markowitz S, Kinzler KW, Vogelstein B and Velculescu VE . (2004). Science, 304, 554.
Sato S, Fujita N and Tsuruo T . (2000). Proc. Natl. Acad. Sci. USA, 97, 10832–10837.
Schmelzle T and Hall MN . (2000). Cell, 103, 253–262.
Scotlandi K, Manara MC, Nicoletti G, Lollini PL, Lukas S, Benini S, Croci S, Perdichizzi S, Zambelli D, Serra M, Garcia-Echeverria C, Hofmann F and Picci P . (2005). Cancer Res., 65, 3868–3876.
Sellers WR and Sawyers CA . (2002). Prostate Cancer Principles and Practice Kantoff Pw (ed). Lippincott Williams & Wilkins: Philadelphia.
Semenza GL . (2003). Nat. Rev. Cancer, 3, 721–732.
Shayesteh L, Lu Y, Kuo WL, Baldocchi R, Godfrey T, Collins C, Pinkel D, Powell B, Mills GB and Gray JW . (1999). Nat. Genet., 21, 99–102.
Solit DB, Basso AD, Olshen AB, Scher HI and Rosen N . (2003). Cancer Res., 63, 2139–2144.
Staal SP . (1987). Proc. Natl. Acad. Sci. USA, 84, 5034–5037.
Steck PA, Pershouse MA, Jasser SA, Yung WK, Lin H, Ligon AH, Langford LA, Baumgard ML, Hattier T, Davis T, Frye C, Hu R, Swedlund B, Teng DH and Tavtigian SV . (1997). Nat. Genet., 15, 356–362.
Stiles B, Gilman V, Khanzenzon N, Lesche R, Li A, Qiao R, Liu X and Wu H . (2002). Mol. Cell. Biol., 22, 3842–3851.
Sun M, Wang G, Paciga JE, Feldman RI, Yuan ZQ, Ma XL, Shelley SA, Jove R, Tsichlis PN, Nicosia SV and Cheng JQ . (2001). Am. J. Pathol., 159, 431–437.
Suzuki H, Freije D, Nusskern DR, Okami K, Cairns P, Sidransky D, Isaacs WB and Bova GS . (1998). Cancer Res., 58, 204–209.
Tabellini G, Tazzari PL, Bortul R, Billi AM, Conte R, Manzoli L, Cocco L and Martelli AM . (2004). Br. J. Haematol., 126, 574–582.
Tashiro H, Blazes MS, Wu R, Cho KR, Bose S, Wang SI, Li J, Parsons R and Ellenson LH . (1997). Cancer Res., 57, 3935–3940.
Thimmaiah KN, Easton JB, Germain GS, Morton CL, Kamath S, Buolamwini JK and Houghton PJ . (2005). J. Biol. Chem., 11 July [E-pub ahead of print].
Thompson FH, Nelson MA, Trent JM, Guan XY, Liu Y, Yang JM, Emerson J, Adair L, Wymer J, Balfour C, Massey K, Weinstein R, Alberts DS and Taetle R . (1996). Cancer Genet. Cytogenet., 87, 55–62.
Treins C, Giorgetti-Peraldi S, Murdaca J, Semenza GL and Van Obberghen E . (2002). J. Biol. Chem., 277, 27975–27981.
Trotman LC, Niki M, Dotan ZA, Koutcher JA, Di Cristofano A, Xiao A, Khoo AS, Roy-Burman P, Greenberg NM, Van Dyke T, Cordon-Cardo C and Pandolfi PP . (2003). PLoS Biol., 1, E59.
Tsao H, Zhang X, Benoit E and Haluska FG . (1998). Oncogene, 16, 3397–3402.
Van de Sande T, Roskams T, Lerut E, Joniau S, Van Poppel H, Verhoeven G and Swinnen JV . (2005). J. Pathol., 206, 214–219.
Vlietstra RJ, van Alewijk DC, Hermans KG, van Steenbrugge GJ and Trapman J . (1998). Cancer Res., 58, 2720–2723.
Wang S, Gao J, Lei Q, Rozengurt N, Pritchard C, Jiao J, Thomas GV, Li G, Roy-Burman P, Nelson PS, Liu X and Wu H . (2003). Cancer Cell, 4, 209–221.
Wang SI, Parsons R and Ittmann M . (1998). Clin. Cancer Res., 4, 811–815.
Wang SI, Puc J, Li J, Bruce JN, Cairns P, Sidransky D and Parsons R . (1997). Cancer Res., 57, 4183–4186.
Ward S, Sotsios Y, Dowden J, Bruce I and Finan P . (2003). Chem. Biol., 10, 207–213.
Warshamana-Greene GS, Litz J, Buchdunger E, Garcia-Echeverria C, Hofmann F and Krystal GW . (2005). Clin. Cancer Res., 11, 1563–1571.
Wolk A, Mantzoros CS, Andersson SO, Bergstrom R, Signorello LB, Lagiou P, Adami HO and Trichopoulos D . (1998). J. Natl. Cancer Inst., 90, 911–915.
Workman P . (2004). Biochem. Soc. Trans., 32, 393–396.
Xu J, Zheng SL, Carpten JD, Nupponen NN, Robbins CM, Mestre J, Moses TY, Faith DA, Kelly BD, Isaacs SD, Wiley KE, Ewing CM, Bujnovszky P, Chang B, Bailey-Wilson J, Bleecker ER, Walsh PC, Trent JM, Meyers DA and Isaacs WB . (2001). Am. J. Hum. Genet., 68, 901–911.
Xu J, Zheng SL, Komiya A, Mychaleckyj JC, Isaacs SD, Hu JJ, Sterling D, Lange EM, Hawkins GA, Turner A, Ewing CM, Faith DA, Johnson JR, Suzuki H, Bujnovszky P, Wiley KE, DeMarzo AM, Bova GS, Chang B, Hall MC, McCullough DL, Partin AW, Kassabian VS, Carpten JD, Bailey-Wilson JE, Trent JM, Ohar J, Bleecker ER, Walsh PC, Isaacs WB and Meyers DA . (2002). Nat. Genet., 32, 321–325.
You MJ, Castrillon DH, Bastian BC, O'Hagan RC, Bosenberg MW, Parsons R, Chin L and DePinho RA . (2002). Proc. Natl. Acad. Sci. USA, 99, 1455–1460.
Zhong H, Chiles K, Feldser D, Laughner E, Hanrahan C, Georgescu MM, Simons JW and Semenza GL . (2000). Cancer Res., 60, 1541–1545.
About this article
Cite this article
Majumder, P., Sellers, W. Akt-regulated pathways in prostate cancer. Oncogene 24, 7465–7474 (2005). https://doi.org/10.1038/sj.onc.1209096
- prostate cancer
- phosphoinostide 3-kinase
Role of the PI3K/Akt pathway in cadmium induced malignant transformation of normal prostate epithelial cells
Toxicology and Applied Pharmacology (2020)
Cardiac Contractility Modulation Attenuates Chronic Heart Failure in a Rabbit Model via the PI3K/AKT Pathway
BioMed Research International (2020)
Prostate Cancer and Prostatic Diseases (2020)
Nature Reviews Cancer (2020)
Ginsenoside Rh4 suppresses aerobic glycolysis and the expression of PD-L1 via targeting AKT in esophageal cancer
Biochemical Pharmacology (2020)