Leaders in Pharmaceutical Business Intelligence (LPBI) Group

Author: Ziv Raviv PhD

Word Cloud By Danielle Smolyar

Part A: Introduction to the PI3K/Akt pathway

Background

Akt/Protein kinase B (PKB) is a cytosolic serine/threonine kinase that promotes cell survival by inactivation of targets of the apoptotic pathways [1], and is implicated in the execution of many other cellular processes including:  cell proliferation, angiogenesis, glucose metabolism [2], protein translation, and gene transcription, all are mediated by extracellular and intracellular signals. In many cancers Akt is overexpressed and has central role in cancer progression and cancer cell survival [3,4], what makes it an attractive target for cancer therapy.

The Akt signaling pathway

Upstream signaling:

The Akt signaling pathway is initiated by growth factors leading to the recruiting and activation of phosphoinositol-3-kinase (PI3K) on receptor tyrosine kinases (RTKs). PI3K is then translocated to the cell membrane where it phosphorylates inositol ring at the D3 position of phosphatidylinositol  to form phosphatidylinositol (3,4,5)-triphosphate (PIP3). PIP3 serves to anchor Akt to the plasma membrane where it is phosphorylated at Thr308 by PDK1 and is further completely activated by mTOR by phosphorylation of Ser473. In certain circumstances activated Ras can also activate PI3K.

Downstream signaling:

Upon activation Akt is transducing its signals to downstream substrates to induce various intracellular processes, among them are: Activation of mTOR and its downstream effector S6K – to facilitate activation of translation; Phosphorylation of Bad – that inhibits apoptosis ; Phosphorylation of the tumor suppressor gene FOXO1 – inducing its ubiquitination and subsequent degradation by the proteasome;  Inhibition by phosphorylation of glycogen synthase kinase 3 (GSK-3) – which results in increase of glycogen synthesis.   Regulation of cell growth and survival is executed also by blocking apoptosis by Akt-associated survivin (BRC5) upregulation and via the NF-κB pathway by activation of IκB kinase (IKK).

• Watch a Video on Akt Signaling Pathway

Figure 1: The Akt signaling pathway

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Taken from: Targeting the PI3K-AKT-mTOR pathway: progress, pitfalls, and promises. Workman P et al. Curr Opin Pharmacol. 2008 Aug;8(4):393-412

Negative regulation:

PI3K-dependent Akt activation is negatively regulated by the tumor suppressor protein PTEN, which works essentially opposite to PI3K, namely,  PTEN acts as a phosphatase and dephosphorylates PIP3 back to PIP2. This step removes Akt from its membrane anchoring through PIP3 resulting in substantial decreased rate of Akt activation and consequently inactivation of Akt-depended downstream pathways. In addition, PIP3 can also be dephosphorylated by the SHIP family of inositol phosphatases form PIP2.

Involvement of Akt  in cancer

The PI3K/Akt pathway is frequently altered and deregulated in many human malignancies. Hyper-activation of AKT kinases is one of the most common molecular findings in human malignancies and account for malignant transformation. Mechanisms for Akt pathway activation include loss of tumor suppressor PTEN function, amplification or mutation of PI3K, amplification or mutation of Akt, activation of growth factor receptors, inactivation of the translation repressor protein 4E-BP1 [5], and exposure to carcinogens [3 ,4]. For instance, heterozygous deletion of PTEN in mice elicits spontaneous tumors attributed mainly to activation of Akt. In addition, the production PIP3 by PI3K is over-activated in a wide range of tumor types. On the other hand, Akt knockout mice demonstrate that Akt is required for both cancer cell survival and oncogenic transformation. That activation of Akt is oncogenic, could be explained by preventing normal apoptosis of cells, thereby enabling accumulation of more oncogenic mutations in these cells. In addition, activation of Akt can also abrogate cell cycle checkpoints and can overcome G2/M cell-cycle arrest mediated by DNA mismatch repair. Thus, cells in which Akt is activated can accumulate mutations because the G2 cell-cycle point is abrogated and survive and continue to divide because of the anti-apoptotic activity of Akt. It is, therefore, proposed that this dual activity of Akt activation may explain the frequent activation of Akt in human malignancies [6].

Taken together, Akt activation has an effective role in cancer and through its downstream substrates Akt controls many cancer related cellular processes such as cell metabolism, growth and survival, proliferation, and motility, all of which contribute to tumor initiation and progression. Therefore, this pathway is an attractive therapeutic target for cancer treatment because it serves as a convergence point for many growth stimuli. Moreover, activation of the PI3/Akt pathway confers resistance to many chemotherapeutic drags [6], and is a poor prognostic factor for many types of cancers. Therefore, small molecule agents that block PI3K/Akt signaling might block many aspects of the tumor-cell phenotype [7,8]. Indeed, the Akt pathway is a major target for anticancer drug development by pharmaceutical companies.

• The below Part B review the efforts to develop targeted Akt therapies for cancer.

Part B: Clinically available/in clinical development PI3K/Akt/mTOR inhibitors 

As described in Part A, the PI3/Akt cascade is a major intracellular signaling route conferring pro-survival signals to the cell. In cancer, there are many conditions where the PI3K/Akt pathway is deregulated, an attribute that is contributing to cancer formation and propagation. Given that Akt servers as convergence point to many pro-survival signals together with it being deregulated frequently in cancers, make Akt as a valuable target for developing anti-cancer therapy.

In addition, Akt shortens patient survival by allowing cancer cells to escape the cytotoxic effects of standard chemotherapy drugs. The importance of the Akt pathway in cancer thus is also evident from its significant role in the resistance of tumors to chemotherapies. A considerable route in developing anti- Akt based therapies is thus combining Akt inhibitors with standard chemotherapy rather than the using of Akt inhibitors as single agents.

Even in targeted therapies for cancer, such those that target receptor tyrosine kinases (RTKs) and other signaling pathways, it has been demonstrated that when applying a targeted agent such as trastuzumab  (Herceptin) a compensation reaction of increasing of downstream and parallel signaling pathways components, among them Akt, occurs in response, which enables cancer cells to be spared the effects of these targeted drugs. Therefore a multi-targeting approach with selective inhibitors would be useful, and inhibiting Akt directly will restore sensitivity to agents such as trastuzumab.

(i) Inhibitors that are in clinical use

Temsirolimus (CCI-779; marked as Torisel by Pfizer), an analog of sirolimus (rapamycin), is an immunophilin-binding antibiotic that blocks the initiation of the translation of mRNA by inhibiting mammalian target of rapamycin (mTOR) in a highly specific manner. Rapamycin itself is toxic and found in the clinic however as an immunosuppressant to prevent rejection in organ transplantation. Temsirolimus acts by interacting with mTOR, preventing the phosphorylation of eIF4E-BP1 and p70S6K, and thereby inhibiting the initiation of the translation of mRNA. The main mechanism of temsirolimus is inhibition of proliferation by G1 phase arrest induction, yet without inducing apoptosis. Temsirolimus was introduced only recently to treat renal cell carcinoma (RCC). In this cancer type HIF-1a levels are accumulated since its degradation is reduced significantly due to mutations of von Hippel Lindau tumor-suppressor gene and the activation of mTOR only worsen that accumulation of HIF1-a, which is its downstream effector. Therefore by blocking mTOR function temsirolimus is reducing the accumulation of HIF-1a. Temsirolimus has been generally well tolerated by advanced RCC patients that could be attributed to its high specificity toward mTOR. However, temsirolimus is associated with a small, but significant increased risk of developing a fatal adverse event. Nevertheless, temsirolimus benefit the overall patient population with the approved indications, including RCC. In the pivotal phase III study, temsirolimus demonstrated median overall survival (OS) in previously untreated patients of 10.9 months in patients with advanced RCC with poor prognostic risk, compared with 7.3 months for interferon-alpha. Temsirolimus remains the only treatment that shows a significant improvement in OSin treatment-naive, poor-risk patients with advanced RCC. Temsirolimus approved cancer indications are RCC and mantle cell lymphoma (MCL), and many other cancer conditions are found in advanced clinical development processes, including various solid tumors, diffused tumors (leukemias and lymphomas), and even in soft tissue sarcomas (STS).

Everolimus (RAD001; marketed by Novartis  as Afinitor) is an ester derivative of rapamycin and is also an inhibitor mTOR.  The drug inhibits oncogenic signaling in tumor cells and angiogenic signaling in vascular endothelial cells. Key features of everolimus include good tolerability, unique mechanism of action, G1 arrest, and induction of apoptosis. In vitro studies have demonstrated a cooperative effect between everolimus and gefitinib in various cancer cell lines. Treatment of human cancer cell lines with everolimus results in a decrease in p-4E-BP1, p-p70S6K, and p-S6 levels while increasing p-AKT levels. The rise of p-AKT is accompanied with a parallel increase in downstream p-GSK-3a/ß, suggesting feedback activation of the AKT pathway. Thus AKT activation could revert the antitumor activity of everolimus. Gefitinib completely prevents everolimus-induced p-AKT increase and markedly enhances the everolimus mediated decrease in p-4E-BP1 and p-p70S6K.

Everolimus is approved for the treatment of RCC, progressive pancreatic neuroendocrine tumors, breast cancer in post-menopausal women with advanced hormone receptor (HR)-positive/HER2-negative. In addition the drug is used as a preventive drug of organ rejection after renal transplantation. As with the case of temsirolimus, everolimus has also a slight increase of mortality risk over other drugs.

Cancer indications that are now in clinical development for treatment by everolimus, some of which are in advanced clinical studies, include various forms of leukemias and lymphomas such as AML, ALL CML, T-cell leukemia, diffuse large B-cell lymphoma (DLBCL), non-Hodgkin’s lymphoma (NHL), and MCL. Everolimus is particularly applicable to the treatment of leukemia because mTOR-related messengers, particularly PI3K, AKT, p70S6K kinase and 4E-BP1, are known to be both constitutively activated in hematologic malignancies and interfere with the activity of current anti-leukemia therapy. Solid tumors such as lung, breast, prostate, and colorectal at various stages, as well as brain cancers and STS are also in developmental stages for everolimus treatment.

(ii) Inhibitors that are in advanced clinical development (phase II/III)

Perifosine (KRX-0401) by AEterna Zentaris – among Akt inhibitors under development for cancer therapy, perifosine is found in advanced stages of clinical development and is moving toward phase III clinical trials. It belongs to alkylphosphocholines (ALP) – phospholipid-like molecules – which disrupt lipid-mediated signal transduction pathways that are necessary for tumor cell growth and survival. ALP induce apoptotic cell death in a variety of tumor cell lines. Perifosine primarily acts on the cell membrane where it inhibits signaling that could explain its capability to inhibit Akt, as Akt interaction with PIP3 in the cytosolic face of the plasma cell membrane is essential to its activation. In addition to Akt, perifosine inhibits also JNK and NF-kB, both are also associated with apoptosis, cell growth, differentiation, and survival. In addition to its potential efficacy as a single agent, perifosine may provide synergistic effects when combined with established cancer treatments such as radiotherapy, chemotherapy, tyrosine kinase inhibitors such as commercially available EGFR inhibitors, and endocrine therapies.

Many clinical trials were/are conducted with perifosine in various cancer conditions and settings. Especially successive phase II studies engaged perifosine were with colorectal cancer (CRC), where patients with metastatic disease treated with the combination of capecitabine and perifosine had more than doubled the median time to progression (TTP) of the disease, which led to an ongoing phase III study. Other solid cancer indications phase II studies employing perifosine that had encouraging results include metastatic RCC (mRCC) and non-small lung cancer (NSLC). Perifosine is also exmined in clinical trials with hematological cancers. Advanced stages clinical studies were conducted in multiple myeloma (MM), where patients treated with the combination of perifosine + bortezomib (proteasome inhibitor) and dexamethasone, in which after, a phase III study was conducted on that basis. However, that phase III study was terminated in March 2013 upon recommendation by data safety monitoring board to discontinue the experiment since it was highly unlikely that the trial would achieve a significant difference in progression-free survival (PFS).  Another potential benefit for perifosine has been documented in Waldenström’s macroglobulinemia (WM).  In addition, perifosine is examined in other hematologic cancers such as in AML, CLL and lymphomas.

• Perifosine at clinicaltrails.gov

MK-2206 – MK-2206 by Merck is an allosteric inhibitor of Akt that is currently widely examined in tens of clinical experimentation where some of them are in phase II status.  In preclinical experiments, MK-2206, demonstrated synergistic activity when combined with other targeted therapies, such as erlotinib in NSCLC cell lines, and lapatinib in breast cancer cell lines and in xenograft mice bearing ovarian cancer, MK-2206 treatment led to substantial growth inhibition and sustained inhibition of Akt.

Several phase II research studies employing MK-2206 are in progress, among them found a multicenter study with advanced ovarian cancer resistant to platinum therapy, and another multicenter study with breast cancer patients. Phase I/II study is conducted also for CLL patients. Many others phase I studies are in progress, among them trails testing the combinations of MK-2206 with other targeted drugs as well as chemotherapy. For instance an ongoing phase I study is evaluating the addition of MK-2206 to trastuzumab in patients with solid tumors HER2 positive, or another study is conducted to evaluate MK-2206 in combination with trastuzumab and lapatinib for the treatment of HER2 positive, advanced solid tumors. MK-2206 is testing also in advanced NSCLC with the combination of gefitinib in one study and with erlotinib in another. In another relatively large phase I study, patients with advanced solid tumors were randomized to MK-2206 either given with carboplatin and paclitaxel, docetaxel, or erlotinib. Another study with patients bearing locally advanced or metastatic solid tumors or metastatic breast cancer examined MK-2206 given with and paclitaxel (Taxol). Finally MK-2206 and selumetinib administration was tested in phase I studies in patients with advanced CRC. Other cancer indications that are investigated MK-2206 as single agent or in combination with chemotherapy in phase I studies include prostate cancer,  head and neck cancer, large B cell lymphoma, leukemias such as AML, and melanoma.

• MK-2206 at clinicaltrails.gov

Ridaforolimus (AP23573/MK-8669,; Taltorvic by Merck) – Ridaforolimus is an oral mTOR inhibitor found in several clinical trials. A compressive phase III experiment was conducted with ridaforolimus in metastatic STS and metastatic bone sarcomas (SUCCEED – Sarcoma Multi-Center Clinical Evaluation of the Efficacy of Ridaforolimus) by Merck and Ariad Pharmaceuticals that had presented positive data at the beginning showing that patients that have received ridaforolimus had a median progression-free survival (PFC) – the primary endpoint of the study – of 17.7 weeks compared with 14.6 weeks for those received placebo. However, FDA’s oncologic drugs advisory committee (ODAC) panel (March 2012) did not approved the use of ridaforolimus as maintenance therapy for patients with metastatic soft-tissue sarcoma or bone sarcoma. The committee did not think that a significant difference was observed between the groups in terms of OS and although patients did experience a longer disease-free period before their cancer returned when receiving ridaforolimus, the delay was not significant. There was also a concern regarding side effects. In a complete response letter, (June 2012) the FDA did not approve the SUCCEED application in its present form, therefore, Merck formally withdrawn the marketing authorization application for ridaforolimus for sarcoma. However, Merck still continue experimenting ridaforolimus in other cancer indications. A phase II study is conducted in breast cancer patients examining ridaforolimus alone, ridaforolimus + dalotuzumab, or ridaforolimus + Exemestane. Another phase II study is conducted in female adult patients harboring recurrent or persistent endometrial cancer. A third Phase II study is examining ridaforolimus in patients with taxane-resistant androgen-independent prostate cancer. Many phase I experiments are conducted with ridaforolimus among them: experiment in pediatric patients with solid tumors treated with dalotuzumab given alone or in combination with ridaforolimus; Bicalutamide and ridaforolimus in men with prostate cancer; Combinations of carboplatin/paclitaxel/ridaforolimus in endometrial and ovarian tumors; Safety study examining ridaforolimus  in patients with progressive or recurrent glioma, and others. Given the consequences as with the SUCCEED experiment; it remains to see whether ridaforolimus alone or in combinations would be approved and be valid in the clinical arena.

• Ridaforolimus at clinicaltrails.gov

RX-0201 (Archexin) by Rexahn Pharmaceuticals is an antisense oligonucleotide directed toward Akt1 mRNA. RX-0201 was demonstrated to significantly downregulated the expression of AKT1 at both the mRNA and protein levels. In addition combined treatment of RX-0201with several cytotoxic drugs resulted in an additive growth inhibition of Caki-1 clear cell carcinoma cells. In addition, preclinical experiments demonstrated that RX-0201 given at nano-molars as a single agent induced substantial growth inhibition in various types of human cancer cells. Furthermore, in vivo studies using nude mice xenografts have resulted in significant inhibition of tumor growth and tumor formation treated with RX-0201. Therefore RX-0201 was further tested in phase I studies in patients with solid tumors. The only dose limiting toxicity (DLT) observed was Grade 3 fatigue. Phase II studies of RX-0201 were approved thus in advanced RCC. Furthermore, another phase II study was completed last year with encouraging results.  This phase II trial was conducted in metastatic pancreatic cancer, assessing the combination of RX-0201 and gemcitabine. The study enrolled 31 patients and the primary endpoint was overall survival following 4 cycles of therapy with a 6-month follow-up. The study demonstrated that treatment with RX-0201 in combination with gemcitabine resulted in a median survival of 9.1 months compared to the published survival data of 5.65 months for gemcitabine given alone. The most frequently side effects were constipation, nausea, abdominal pain, and pyrexia, regardless of relatedness.

BKM120 – by Novartis is an oral selective class-I PI3K inhibitor, induces its inhibition in an ATP-competitive manner, thereby inhibiting the production of the secondary messenger PIP3 and activation of downstream signaling pathway. BKM120 was shown to induce pro-apoptotic effects in vitro and anti-tumor activity in vivo. BKM120 is enrolled in many clinical trials at all levels for several cancer indications. Phase I experiments are performed with the following cancers: CRC in combination with panitumumab; RCC; breast cancer (HR+/HER2+); breast cancer (triple negative, recurrent); ovarian cancer; and leukemias.  Phase II trials include: endometrial cancer; metastatic NSCLC; malignant melanoma (Braf V600 mutated); prostate; and glioblastoma multiforme (GBM).

A phase III study is currently enrolled with postmenopausal breast cancer patients with HR+/HER2- (local, advanced or metastatic), examining BKM120 in combination with fulvestrant. In preliminary clinical experiments activity was observed with BKM120 in patients with breast cancer, as a single agent or in combination with letrozole, or trastuzumab. In this phase III study, postmenopausal women with HR+/HER2- breast cancer whom were treated with aromatase inhibitor (AI), and are refractory to endocrine and mTOR inhibition (mTORi) combination therapy, are randomized to receive continuous BKM120 or placebo daily, with fulvestrant. The rational for this experiment is that the use of PI3K inhibition may overcome resistance to mTORi in breast cancer by targeting the PI3K pathway upstream.  The primary endpoint of the trail is PFS and the secondary endpoint is OS. Other secondary endpoints are overall response rate and clinical benefit rate, safety, pharmacokinetics of BKM120, and patient-reported quality of life.

• BKM120 at clinicaltrails.gov

CAL-101 (Idelalisib) – by Gilead Sciences is an orally bio-available, small molecule inhibitor of PI3K delta proposed for the treatment hematologic malignancies. In preclinical efficacy studies, CAL-101 inhibited the PI3K pathway and decreased cellular proliferation in primary CLL and AML cells, and in a range of NHL cell lines. The delta form of PI3K is expressed primarily in blood-cell lineages, including cells that cause or mediate hematologic malignancies, inflammation, autoimmune diseases and allergies. Therefore, CAL-101 as specific inhibitor of the PI3K-delta is expected to have therapeutic effects in these diseases without inhibiting PI3K signaling that is critical to the normal function of healthy cells. A variety of studies have shown that inhibition of other PI3K forms can cause significant toxicities, particularly with respect to glucose metabolism, which is essential for normal cell activity. CAL-101 was shown to block constitutive PI3K signaling, resulting in decreased phosphorylation of Akt and other downstream effectors, an increase in PARP and caspase cleavage, and an induction of apoptosis across a broad range of immature and mature B-cell malignancies. Importantly, CAL-101 does not promote apoptosis in normal T cells or NK cells, nor does it diminish antibody-dependent cellular cytotoxicity (ADCC) but decreased activated T-cell production of various inflammatory and anti-apoptotic cytokines. These findings provide rationale for the clinical development of CAL-101 as a first-in-class targeted therapy for CLL and related B-cell proliferative disorders. Indeed several clinical trials are currently enrolled for Hodgkin’s lymphoma, NHL, and CLL. Phase III clinical trials for CLL are now recruiting patients aimed to examine CAL-101 in combination with Bendamustine and Rituximab in one study;  CAL-101 + Rituximab;  and the combinations of CAL-101 with Ofatumumab in third phase III study. Both Rituximab and Ofatumumab are monoclonal Abs for CD20, which is primarily found on the surface of B cells. In addition, another phase III study of CAL-101 in combination with Bendamustine and Rituximab for indolent NHLs is also now recruiting patients.

• CAL-101 at clinicaltrials.gov

(iii) Other Akt pathway inhibitors in clinical development.

There are dozens of agents targeting Akt pathway that are found at preclinical and clinical development. The various inhibitors are targeting various elements of the Akt pathway including: Akt itself, PI3K, mTOR, and PDK1. Most of these agents are small molecules inhibitors, some are extracts while others are synthetic, but also include an antisense oligonucleotide (RX-0201 to Akt).

The list below describes shortly agents which currently reached phase II stage and their relevant indications:

XL-147 – sponsored by Sanofi, small molecule-pan PI3K inhibitor for breast cancer and endometrial cancer.

XL-765 – also of Sanofi, inhibitor of the activity of PI3K and mTOR, for HR+/HER2- breast cancer patients.

BN108 – by Bionovo, an aqueous extract of Anemarrhena asphodeloides, is an orally available dual inhibitor, that induces apoptotic cancer cell death by rapid inactivation of both Akt and mTOR pathways, for breast cancer.

GDC-0068 – by Genentech, is an orally available small molecule pan-Akt inhibitor, for prostate cancer.

BEZ235 – by Novartis is a dual ATP-competitive PI3K and mTOR inhibitor, prevents PI3K signaling and inhibits growth of cancer cells with activating PI3K mutations. Phase II study is recruiting patients with metastatic or unresectable malignant PEComa (perivascular epithelioid cell tumors), other phase II include endometrial cancer indications and metastatic HR+/HER2-breast cancer patients.

BAY 80-6946 – is a pan class I PI3K inhibitor by Bayer. Phase II for NHL, currently recruiting.

Nelfinavir  – by ViiV Healthcare is an HIV protease inhibitor found to downregulate Akt phosphorylation by inhibiting proteasomal activity and inducing the unfolded protein response (UPR). HIV-1 protease inhibitor was found induces growth arrest and apoptosis of human prostate cancer cells in vitro and in vivo in conjunction with blockade of androgen receptor, STAT3 and AKT signaling. A phase I/II trial is enrolled for patients with locally advanced CRC to test Nelfinavir in combination with chemo/radiotherapy.

Triciribine – Triciribine phosphate monohydrate (TCN-PM) is a specific AKT inhibitor used also in the basic research arena but undergo also several clinical studies. Currently a phase II sponsored by Cahaba Pharmaceuticals is recruiting, to examine triciribine with paclitaxel in patients with locally advanced breast cancer. And a phase I/II experiment of combination with carboplatin in ovarian patients is planned.

GSK2110183 – by GlaxoSmithKline  is an oral pan–Akt inhibitor. Phase II is recruiting subjects with solid tumors and hematologic malignancies.

(iv) Conclusive remarks

Given the broaden arsenal of agents targeting Akt that are in pre-clinical and clinical development, it is extremely important to figure out how to use them optimally and to elucidate carefully which of them have the greatest potential to proceed into advanced stages of clinical trials and to clinical approval.  One of the various considerations in developing valid Akt inhibitors for the clinic use should be choosing a relevant cancer in which Akt has a central role in its development/propagation (e.g. mRCC). Since there is cross-talk between the Akt pathway to other pathways especially by involvement of RTKs (e.g. VEGFR), there is a rational to apply Akt inhibitions in cancer indications that had good results with inhibition of RTKs where combinations of Akt with agents such as sunitinib, could results in a synergistic anti-cancer effect. The combinations of Akt inhibitors with RTKs inhibitors could also overcome the compensate reaction to agents such as Herceptin that confer resistance. It is important to introduce efficient Akt inhibitor on the background of existing anti-cancer chemotherapies where Akt inhibitors can complement these therapies by circumvent frequent resistance to these drugs. Finally, the developing of biomarkers for a validation of the efficacy of candidate Akt inhibitor to be developed in further advance clinical studies for specific cancer indications is essentially needed, to ensure that accurate efforts would be invested at the most validate Akt inhibitors. Such biomarkers could be levels of phosphorylated Akt in blood or mRNA levels to be monitored upon treatment with Akt inhibitors and the correlation to the efficacy of these inhibitors, and that is besides of their prognostic value. The status of mutations of PI3K and PTEN could also serve as a marker for the efficiency of Akt inhibitors and how to use them optimally.

References

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5. She QB, Halilovic E, Ye Q, Zhen W, Shirasawa S, Sasazuki T, Solit DB, Rosen N (2010) 4E-BP1 is a key effector of the oncogenic activation of the AKT and ERK signaling pathways that integrates their function in tumors. Cancer Cell 18 (1):39-51

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9. Alexander W (2011) Inhibiting the Akt pathway in cancer treatment. P T.  April; 36(4): 225–227

10. LoPiccolo J, Blumenthal GM, Bernstein WB, Dennis PA.(2008) Targeting the PI3K/Akt/mTOR pathway: effective combinations and clinical considerations. Drug Resist Updat.  Feb-Apr;11(1-2):32-50

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Resources

New medicine Oncology KnowledgeBASE (nmOK)

ClinicalTrials.gov

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