Targeting the metabolism system

Incidence and disease specific mortality in prostate cancer exhibit marked global variation with the highest levels seen in Western Europe, North America and the lowest in Asia [53]. It is assumed that whilst this is accounted for by a significant genetic component, that diet and lifestyle factors may also contribute. Epidemiological studies also support an association between dietary fat intake, poor prognosis and risk of relapse [54]. In order to identify new pathways that are important in prostate cancer pathogenesis, evaluating a role for the metabolism system and its key components is crucial.

Cancer cells are already known to differ from normal cells in some of the fundamental metabolic pathways they employ. Most cancer cells generate energy by primarily metabolizing glucose by glycolysis followed by lactate production. This occurs in contrast to normal cells in which glucose is catabolised by oxidative phosphorylation, a primarily aerobic process. Proliferating cancer cells also exhibit increased glucose uptake compared to normal cells. This results in tumour cells with glycolytic rates over 200 times higher than those of normal tissues and allows efficient generation of macromolecules needed for new cancer cell production. This so-called Warburg hypothesis was initially thought to be the fundamental cause of cancer, however it is now thought to explain how tumours may flourish in low oxygen environments [55]. These observations suggest that differences in metabolism between normal tissues and cancer cells may be important in oncogenesis.

Insulin and insulin-like growth factors (IGF-1) are extracellular hormones and growth factors that regulate important metabolic pathways such as fatty acid and sterol synthesis as well as growth factor signaling via the PI3 kinase and MAP kinase pathways. Their activation may stimulate tumourigenesis by activating one or both of these mitogenic pathways and disrupting fat metabolism.

IGF-I and IGF-II bind to the IGF-1 receptor, a tyrosine kinase receptor that is known to be upregulated following castration in animal models [56]. It has been implicated in the development of the castrate resistant state with evidence that inhibition of the IGF-1 receptor may enhance the effect of castration in xenograft models [57]. Targeting the IGF-1 receptor is therefore an attractive therapeutic target in CRPC. Several IGF-1 receptor inhibitors are currently being evaluated in clinical trials and candidates include both monoclonal antibodies and small molecule tyrosine kinase inhibitors. Cixutumumab (or IMC-A12) is a fully human IgG1 subclass monoclonal antibody that has reached phase II of clinical development. A single agent study of chemotherapy naïve asymptomatic patients noted that the drug was well tolerated with grade 3 fatigue and hyperglycaemia the worst toxicity seen and 29% of patients had stable disease [58]. Future trials with this agent are planned or ongoing including in the first line metastatic setting with androgen deprivation therapy (SWOG S0925) based on supporting preclinical data [57].

Drug

Class

Study Design

Results

Current phase of clinical development

Reference

Insulin-like growth factor receptor inhibitors

Cixitumumab /IMC-A12

IGF-1 R inh

Phase II study in chemo naïve CRPC Asx pts 10mg/kg q2 wkly or 20mg/kg q3 wkly

29% disease stab >6 mths. Worst toxicity G3 fatigue & tglycaemia

Phase II Neoadj +ADT in high risk pts

+ Temsiro in met CRPC

+ 1st line met+ADT

[58]

Figitumumab /CP-751871

IGF-1 R inh

Phase Ib in adv solid tumours in comb with docetaxel 75mg/m2

46 pts - MTD not reached. 4PR and 12 pts with disease stab >6months. G3/4 febrile neutropenia, fatigue 10/18 CRPC pts had >5 CTC with 60% response

Phase III studies recruiting in NSCLC (ADVIGO 1016). Phase II in breast, prostate, colorectal & Ewings sarcoma

[59, 60]

Ganitumab/ AMG 479

IGF-1 R inh

Phase I dose escalation study in adv solid malign of IV q2 wkly

53 pts - 1DLT - G3 ¿plts & transminitis. MTD not reached - maxdose 20mg/kg. t in serum IGF-1

Phase II studies recruiting in Ex Stage small cell with platinum, +Everolimus in colorectal, in carcinoid & pNETs

[61]

Lisitinib/ 0SI-906

Dual kinase inhibitor of Insulin & IGF-1 R

Phase I continuous dose escalation study in adv solid tumours using BID & QD dosing Phase I intermittent dosing in adv solid tumours

57 pts - MTD reached 400mg QD, 150mg BID. DLTs were t QTc & G3 hyperglycaemia SD >12 weeks seen in 18/43 pts MTD 600 mg

Phase III recruiting in Adrenocortical Ca

Phase II + Erlotinib in Breast

[62, 116]

AMP Kinase activators

AICAR

(Aminoimidazole-4

-caboxamide-1-b-

riboside

AMP mimetic

Preclinical studies show inhibition of prostate cancer cell proliferation

Inhibition of tumour growth in prostate cancer xenograft models

[78, 117]

A-769662

AMP K

Delay tumour

[79]

subunit act.

development & decrease

tumour incidence in

PTEN def mice

Metformin

Indirect

44% reduction in

Phase II recruiting

[80]

prostate cancer cases

in loc adv or met

compared to Caucasian

CRPC and in loc

controls

disease as

prevention against

MS with ADT

Resveratrol

Indirect

Phase I single dose safety

Results are awaited

Phase I/II currently

[82]

study in colon ca pts with

recruiting as neoadj

hepatic metastases

in colon carcinoma

pts

mTOR inhibitors

Temsirolimus

mTOR

Phase II study in CRPC

Currently recruiting

Phase II recruiting

[118]

inhibitor

patients post first line

in chemo naïve

docetaxol

CRPC pts, in comb

chemotherapy. Pts

with cixutumumab

receive maintenance

in met CRPC, in

temsirolimus 25mg/m2

CRPC after no

weekly

response to chemo

with bevacizumab

& PI/II with

docetaxel

Everolimus

mTOR

Phase II study in castrate

In vivo evidence of

Phase I/II in met

[72, 73, 74]

inhibitor via

resistant prostate cancer

synergy between mTOR

CRPC with

mTORC1

of bicalutamide and

and AR pathways.

docetaxel &

everolimus compared to

Study ongoing but 8 pts

bevacizumab, in

bicalutamide alone

enrolled. 6/8 responses

post chemo pts

in PSA. Well tolerated

with carbo/pred, in

with no unexpected

neoadj setting in

toxicity

int/high risk

localized disease &

in first line met/

locally adv setting

PI3 kinase inhibitors

XL-147

Class I PI3K

Phase I dose escalation

68pts - DLT G3 rash.

Recruiting to Phase

[65]

isoform

study in adv solid malig

Inhibition of PI3K & ERK

I study in solid

inhibitor

of continuous daily

demonstrated.

tumours and Phase

dosing or d1-21 of 28

Prolonged stable disease

I/II in breast &

day cycle

observed

endometrial

carcinoma

GDC-0941

Pan PI3K inhibitor

Phase I dose escalation study. GDC-0941 given QD for 21 out of 28 day cycle. BID cohorts also recruited

36 pts enrolled, dose escalation ongoing. QD dosing safe up to 254mg, BID dosing safe up to 180mg. 3 DLTs -headache, pl eff and red TLCO

Phase I study recruiting in NSCLC & Met breast cancer in comb. With paclitaxel or carbo +/- bevacizumab

[66]

BKM120 BEZ235

Pan class I PI3K inhibitor

Phase I dose escalation study. BKM120 PO QD

30 pts enrolled from 12.5-150mg. MTD 100mg. PD data suggests active drug at 100mg. 8/10 PR on FDG-PET

Phase I/II currently accruing in HER2+ Met breast ca. Also recruiting in combination with GSK 1120212

[67]

Akt inhibitors

GSK2141795 GSK2110183

Akt inhibitor

First-in-human phase I study of GSK 2141795 in advanced solid malig, also recruiting in combination with GSK 1120212

Perifosine

Oral Akt inhibitor

CRPC pts with rising PSA but no detectable mets. 900mg loading dose then 100mg daily

20% pts had a PSA reduction but did not meet PSA response criteria. DLTs included hypoNa, arthritis, photophobia, hyperuricaemia

Recruiting phase III in multiple myeloma with bortezomib +/-dex , phase I in recurrent paediatric solid tumours

[70]

MK2206

Highly selective non ADP comp Akt inhibitor

Phase I dose escalation study 30-90mg QOD in 28 day cycles in tx-refractory solid tumours

MTD established at 60mg QOD. PD efficacy confirmed with dec pAKT levels. SD seen in 6/19 pts

Phase II

bicalutamide +/-MK2206 in pts after local therapy + rising PSA, Phase I in com with docetaxel is recruiting

[71]

Table 2. The Metabolic Syndrome

Table 2. The Metabolic Syndrome

A second IGF-1 receptor antibody is the human IgG2 subclass antibody figitumumab. This was evaluated in a phase I dose escalation trial during which the maximum feasible dose was established as 20mg/kg intravenously every 21 days [59]. A phase Ib dose escalation study in combi nation with docetaxel then enrolled 46 predominantly metastatic CRPC patients. This combination was well tolerated with no MTD reached and the toxicity profile included nausea, febrile neutropenia, anorexia, fatigue and hyperglycaemia. A 22% response rate was observed with a disease stabilization rate of 44% for > 6 months [60]. A phase II study of this combination has completed accrual and results are awaited. A third monoclonal antibody ganitumumab (or AMG478, Amgen) is also in clinical development and whilst safe in phase I dose escalation studies, its focus for ongoing development is in lung and colorectal carcinoma [61]. 0SI-906 or linsitinib is a first in class inhibitor of both the insulin and IGF-1 receptors. It has been evaluated in phase I dose escalation safety studies where MTDs of 400mg QD and 150 mg BID were reached. The dose limiting toxicities were the known class effects hyperglycaemia and prolongation of the QTc interval. Whilst further development of this compound continues in adreno-cortical and breast carcinomas [62], a phase II study of linsitinib in asymptomatic or mildly symptomatic CRPC patients has completed accrual and results are awaited.

An important downstream intracellular signaling pathway that has been implicated in prostate cancer pathogenesis, progression and the development of castration resistance is the PI3K/Akt/mTOR pathway. Phosphatidylinositol-3 kinase (PI3K) activation results in the phos-phorylation of phosphatidylinositol 4,5-bisphosphate (PIP2) to generate the second messenger phosphatidylinositol 3-5triphosphate (PIP3) that activates the Akt signal transduction cascade. Reports suggest that PI3K signaling may play a critical role in castration resistance allowing prostate cancers to maintain continued proliferation in low androgen environments [63]. In addition, the PI3K isoforms p85 and p110b appear to have a role in regulating AR-DNA interactions and the assembly of the AR based transcriptional complex [64]. There are numerous PI3K inhibitors in clinical development, XL147 (Exelixis) is a class I isoform inhibitor whilst SF1126 (Semafore), GDC0941 (Genentech) and BEZ234 (Novartis) are pan PI3K inhibitors. All agents have successfully completed phase I dose escalation studies and preliminary results suggest that these agents are well tolerated and have favourable pharmacokinetic-pharmacodynamic profiles [65 - 67]. Further tumour specific phase I/II studies are ongoing, although at present no prostate specific studies are in progress.

The Akt's are a family of three serine/threonine kinases - AKT-1, AKT-2, & AKT-3. Phos-phorylation of AKT modulates multiple downstream cellular functions including apoptosis, metabolism and proliferation. Enhanced pAKT correlates with more aggressive histological and pathological prostate cancer stage, and a worse prognosis underlining its importance as a druggable target and possible role as a prognostic biomarker [68, 69]. There are several classes of Akt inhibitors currently in clinical development including those inhibiting the catalytic and the pleckstrin homology (PH) domains. Perifosine, an alkylphospholipid inhibiting the PH domain has reached phase II in CRPC patients. Unfortunately although well tolerated this agent did not exhibit significant activity [70]. The pan-AKT inhibitors GSK2141795 and MK2206 with simultaneous targeting of both AKT-1 and AKT-2 are considered potentially superior to single isoform inhibitors. MK2206 was well tolerated in a phase II dose escalation study with an observed MTD of 60mg. Pharmacodynamic endpoints were met with a measurable reduction in pAKT levels. In addition, 6 of 19 patients achieved stable disease [71]. Further development continues in a number of tumour types both as single agent and in combination with chemotherapy. Of note a phase I study in combination with docetaxel is currently recruiting, as is a randomized phase II study of bicaluta-mide +/- MK2206 in prostate cancer patients with a rising PSA after definitive local therapy. GSK2141795 and GSK 2110183 also entered phase I development with results of first in human safety studies pending.

Mammalian target of rapamycin (mTOR) is also a serine/threonine kinase downstream of PI3K which interacts with the mTOR complexes mTORC1 and mTORC2 to regulate cell proliferation and inhibit apoptosis. Proof of principle that the PI3K pathway can be successfully targeted for clinical use in cancer has been demonstrated by the development of the rapamy-cin analogs - temsirolimus and everolimus that inhibit the mTORC1 kinase. Temsirolimus is an intravenous formulation which was the first compound in this class to be approved by the FDA for first line treatment in poor risk patients with advanced renal cell cancer. Evero-limus an oral formulation is also approved for use in advanced renal cell cancer but in the second line setting. Single agent studies of these agents in the prostate cancer setting have been performed but were considered disappointing with a short time to progression (2.5 months) and no radiographic or PSA responses [72]. Everolimus has also been evaluated in combination with docetaxel in CRPC patients. The recommended phase II dose was 10mg everolimus and 70mg/m2 docetaxel, 3 patients had a PSA response and the combination was well tolerated with fatigue and haematological toxicities the most common [73]. Further studies with both agents in prostate cancer continue with a similar study involving temsiro-limus in combination with docetaxel, as well as studies with cixitumumab and bevacizu-mab. A randomized study in hormone responsive patients of bicalutamide +/- everolimus is currently recruiting with early results suggesting the combination was well tolerated with PSA responses observed in six of eight patients [74]. Studies in the neoadjuvant and localized disease setting are also ongoing.

Finally, AMP kinase is a serine/threonine kinase that is activated by metabolic stressors that deplete ATP and increase AMP levels. Its activity is also under the control of hormones such as adiponectin and leptin as well as cytokines [75]. The activation of AMP kinase reduces insulin levels, as well as increasing ATP producing activities (glucose uptake, fatty acid oxidation) and suppressing ATP-consumption (synthesis of fatty acids, sterols, glycogen and proteins). AMP kinase therefore acts as a metabolic switch controlling glucose and lipid metabolism. Decreased AMP kinase activity is thought to contribute to the metabolic abnormalities involved in the metabolic syndrome [76]. In addition polymorphisms in a gene locus encoding one of the AMPK subunits correlates with prostate cancer risk [77].

Activators of AMP kinase activity may be direct or indirect. Several direct AMP kinase activators act either by allosteric binding to AMP kinase subunits or as an AMP mimetic. These agents aminoimidazole-4-caboxamide-1-b-riboside (AICAR), A-769662 and PT1 are at an early stage of clinical development. AICAR has been shown to inhibit prostate cancer cell proliferation and tumour growth in xenograft models [78]. However its further development may be limited by its poor specificity for AMPK and low oral bioavailability. To date no interventional oncology studies have been undertaken. The recent publication of the crystal structure of AMP kinase subunits has allowed rational drug design of A-769662 and

PT1. A769662 has been shown to delay tumour development and decrease tumour incidence in PTEN deficient mice [79].

The indirect activator metformin is a well established treatment for type II diabetes mellitus. Its use is associated with a 44% risk reduction in prostate cancer cases compared with controls in Caucasian men [80]. The mechanism of metformin's antitumour effect is not completely understood, although it is hypothesized that metformin may decrease circulating glucose, insulin and IGF-1 levels by inhibiting hepatic gluconeogenesis resulting in increased signaling through the insulin/IGF-1 pathway [81]. Its action in prostate cancer is currently under evaluation in a number of clinical trials, these include as a preventative treatment for metabolic syndrome in men on androgen deprivation therapy and as first line therapy in locally advanced or metastatic prostate cancer patients. Finally, resveratrol is a phytoalexin produced by plants when under attack by pathogens. It is found in the skin of grapes, grape products, red wine and mulberries and is thought to have anticancer properties. These were first identified when it was shown to inhibit tumourigenesis in a mouse skin cancer model [82]. Its indirect action on AMP kinase remains to be elucidated although its anticancer action has been explored in a number of tumour types. Clinical trials using re-sveratrol have explored potential roles in preventing and treating diabetes, Alzheimers disease and weight loss. In addition safety studies of its use in colorectal carcinoma patients with liver metastases have been conducted and the results are awaited. As yet no studies in prostate cancer are planned.

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