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Posts Tagged ‘PI3K/AKT pathway’


Infinity and AbbVie partner to develop and commercialise Duvelisib for cancer… for the treatment of chronic lymphocytic leukemia.

Duvelisib is a dual phosphoinositide-3-kinase (PI3K) delta and PI3K gamma inhibitor.  The delta and gamma isozymes are selectively expressed in leukocytes.    This article (at Dr. Melvin Crasto’s blog newdrugapprovals.org) discusses the synthesis of Duvelisib and mentions additional clinical trials underway including a phase II trial for the treatment of patients with mild asthma undergoing allergen challenge, for the treatment of rheumatoid arthritis and for the treatment of refractory indolent non-Hodgkin’s lymphoma. Phase I clinical trials for the treatment of advanced hematological malignancies (including T-cell lymphoma and mantle cell lymphoma).  The drug was originally developed at Takeda subsidiary Intellikine.

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Larry H. Bernstein, MD, FCAP, reviewer and curator

https://pharmaceuticalintelligence.com/2013-12-09/larryhbern/VEGF-activation-and-signaling,-lysine-methylation,-and-activation-of-receptor-tyrosine-kinase

Lysine Methylation Promotes VEGFR-2 Activation and Angiogenesis

 Edward J. Hartsough1*, Rosana D. Meyer1*, Vipul Chitalia2, Yan Jiang3, Victor E. Marquez4, Irina V. Zhdanova5, Janice Weinberg6, Catherine E. Costello3, and Nader Rahimi1{dagger}
 1 Departments of Pathology and Ophthalmology, School of Medicine, Boston University Medical Campus, Boston, MA 02118, USA.
2 Harvard-MIT Division of Health Science and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
3 Department of Biochemistry and Center for Biomedical Mass Spectrometry, School of Medicine, Boston University Medical Campus, Boston, MA 02118, USA.
4 Chemical Biology Laboratory, National Cancer Institute at Frederick, Frederick, MD 21702, USA.
5 Department of Anatomy and Neurobiology, Boston University Medical Campus, Boston, MA 02118, USA.
6 School of Public Health, Boston University Medical Campus, Boston, MA 02118, USA.
Activation of vascular endothelial growth factor receptor-2 (VEGFR-2), an endothelial cell receptor tyrosine kinase,
  • promotes tumor angiogenesis and ocular neovascularization.
We report the methylation of VEGFR-2 at multiple Lys and Arg residues, including Lys1041,
  • a residue that is proximal to the activation loop of the kinase domain.
Methylation of VEGFR-2 was
  • independent of ligand binding and
  • was not regulated by ligand stimulation.
Methylation of Lys1041 enhanced tyrosine phosphorylation and kinase activity in response to ligands. Additionally, interfering with the methylation of VEGFR-2 by pharmacological inhibition or by site-directed mutagenesis revealed that
  • methylation of Lys1041 was required for VEGFR-2–mediated angiogenesis
    • in zebrafish and
    • tumor growth in mice.
We propose that methylation of Lys1041 promotes the activation of VEGFR-2 and that
  • similar posttranslational modification could also regulate the activity of other receptor tyrosine kinases.
{dagger} Corresponding author. E-mail: nrahimi@bu.edu
Citation: E. J. Hartsough, R. D. Meyer, V. Chitalia, Y. Jiang, V. E. Marquez, I. V. Zhdanova, J. Weinberg, C. E. Costello, N. Rahimi, Lysine Methylation Promotes VEGFR-2 Activation and Angiogenesis. Sci. Signal. 6, ra104 (2013).

Phosphoproteomic Analysis Implicates the mTORC2-FoxO1 Axis in VEGF Signaling and Feedback Activation of Receptor Tyrosine Kinases

Guanglei Zhuang, Kebing Yu, Zhaoshi Jiang, Alicia Chung, Jenny Yao, Connie Ha, Karen Toy, Robert Soriano, Benjamin Haley, Elizabeth Blackwood, Deepak Sampath, Carlos Bais, Jennie R. Lill, and Napoleone Ferrara (16 April 2013){dagger}
Sci. Signal. 16 April 2013;  6 (271), ra25.    http://dx.doi.org/10.1126/scisignal.2003572
Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
* These authors contributed equally to this work.{dagger}
{dagger} Present address: Department of Pathology and Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
The vascular endothelial growth factor (VEGF) signaling pathway plays a pivotal role in normal development and
  • also represents a major therapeutic target for tumors and intraocular neovascular disorders.
The VEGF receptor tyrosine kinases promote angiogenesis by phosphorylating downstream proteins in endothelial cells. We applied a large-scale proteomic approach to define
  1. the VEGF-regulated phosphoproteome and
  2. its temporal dynamics in human umbilical vein endothelial cells and then
  3. used siRNA (small interfering RNA) screens to investigate the function of a subset of these phosphorylated proteins in VEGF responses.
The PI3K (phosphatidylinositol 3-kinase)–mTORC2 (mammalian target of rapamycin complex 2) axis emerged as central
  1. in activating VEGF-regulated phosphorylation and
  2. increasing endothelial cell viability
    • by suppressing the activity of the transcription factor FoxO1 (forkhead box protein O1),
    • an effect that limited cellular apoptosis and feedback activation of receptor tyrosine kinases.
This FoxO1-mediated feedback loop not only reduced the effectiveness of mTOR inhibitors at decreasing protein phosphorylation and cell survival
  • but also rendered cells more susceptible to PI3K inhibition.
Collectively, our study provides a global and dynamic view of VEGF-regulated phosphorylation events and
  • implicates the mTORC2-FoxO1 axis in VEGF receptor signaling and
  • reprogramming of receptor tyrosine kinases in human endothelial cells.
{ddagger} Corresponding author. E-mail: nferrara@ucsd.edu
Citation: G. Zhuang, K. Yu, Z. Jiang, A. Chung, J. Yao, C. Ha, K. Toy, R. Soriano, B. Haley, E. Blackwood, D. Sampath, C. Bais, J. R. Lill, N. Ferrara, Phosphoproteomic Analysis Implicates the mTORC2-FoxO1 Axis in VEGF Signaling and Feedback Activation of Receptor Tyrosine Kinases. Sci. Signal. 6, ra25 (2013).

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Resistance to Receptor of Tyrosine Kinase

Curators: Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

Two just published articles in Science Translational Medicine report

(1) the discovery of bypass mechanisms of resistance to the receptor of tyrosine kinase inhibition (rTKI) in lung cancer
(2) receptor signaling networks in predicting drug response

Bypass Mechanisms of Resistance to Receptor Tyrosine Kinase Inhibition in Lung Cancer

Matthew J. Niederst1,2 and Jeffrey A. Engelman1,2*
1 Massachusetts General Hospital Cancer Center, Charlestown, MA
2 Department of Medicine, Harvard Medical School, Boston, MA
Sci. Signal., 24 Sep 2013; 6(294), p. re6
http://dx.doi.org/10.1126/scisignal.2004652

Abstract: Receptor tyrosine kinases (RTKs) are activated by somatic genetic alterations in a subset of cancers, and

  • such cancers are often sensitive to specific inhibitors of the activated kinase.

Two well-established examples of this paradigm include

  • lung cancers with either EGFR mutations or
  • ALK translocations.

In these cancers, inhibition of the corresponding RTK

  • leads to suppression of key downstream signaling pathways, such as
    • the PI3K (phosphatidylinositol 3-kinase)/AKT and
    • MEK (mitogen-activated protein kinase kinase)/ERK (extracellular signal–regulated kinase) pathways,

resulting in cell growth arrest and death.

Despite the initial clinical efficacy of ALK (anaplastic lymphoma kinase) and EGFR (epidermal growth factor receptor) inhibitors in these cancers,

  • resistance invariably develops, typically within 1 to 2 years.

Over the past several years, multiple molecular mechanisms of resistance have been identified, and some common themes have emerged. These are

  1. the development of resistance mutations in the drug target that prevent the drug from effectively inhibiting the respective RTK.
  2. activation of alternative RTKs that maintain the signaling of key downstream pathways
    • despite sustained inhibition of the original drug target.

Indeed, several different RTKs have been implicated in promoting resistance to EGFR and ALK inhibitors in both laboratory studies and patient samples.

In this mini-review, we summarize

  1. the concepts underlying RTK-mediated resistance,
  2. the specific examples known to date, and
  3. the challenges of applying this knowledge to develop improved therapeutic strategies to prevent or overcome resistance.

* Corresponding author. E-mail: jengelman@partners.org

Citation: M. J. Niederst, J. A. Engelman, Bypass Mechanisms of Resistance to Receptor Tyrosine Kinase Inhibition in Lung Cancer. Sci. Signal. 6, re6 (2013).

Profiles of Basal and Stimulated Receptor Signaling Networks Predict Drug Response in Breast Cancer Lines

Mario Niepel1*{dagger}, Marc Hafner1{dagger}, Emily A. Pace2{dagger}, Mirra Chung1, Diana H. Chai2, Lili Zhou1, Birgit Schoeberl2, and Peter K. Sorger1*
1 Harvard Medical School Library of Integrated Network-based Cellular Signatures Center, Department of Systems Biology, Harvard Medical School, Boston, MA
2 Merrimack Pharmaceuticals, Cambridge, MA
Sci. Signal., 24 Sep 2013; 6(294), p. ra84
Abstract: Identifying factors responsible for variation in drug response is essential for the effective use of targeted therapeutics. We profiled signaling pathway activity in a collection of breast cancer cell lines
  • before and after stimulation with physiologically relevant ligands, which
  • revealed the variability in network activity among cells of known genotype and molecular subtype.
Despite the receptor-based classification of breast cancer subtypes, we found that
  • the abundance and activity of signaling proteins in unstimulated cells (basal profile), as well as
  • the activity of proteins in stimulated cells (signaling profile),
varied within each subtype.
Using a partial least-squares regression approach, we constructed models that significantly predicted sensitivity to 23 targeted therapeutics. For example,
  • one model showed that the response to the growth factor receptor ligand heregulin effectively predicted
    • the sensitivity of cells to drugs targeting the cell survival pathway mediated by PI3K (phosphoinositide 3-kinase) and Akt, whereas
    • the abundance of Akt or the mutational status of the enzymes in the pathway did not.
Thus, basal and signaling protein profiles may yield new biomarkers of drug sensitivity and enable the identification of appropriate therapies in cancers characterized by similar functional dysregulation of signaling networks.
* Corresponding author. E-mail: peter_sorger@hms.harvard.edu (P.K.S.); mario_niepel@hms.harvard.edu (M.N.)
Citation: M. Niepel, M. Hafner, E. A. Pace, M. Chung, D. H. Chai, L. Zhou, B. Schoeberl, P. K. Sorger, Profiles of Basal and Stimulated Receptor Signaling Networks Predict Drug Response in Breast Cancer Lines. Sci. Signal. 6, ra84 (2013).

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Author: Ziv Raviv PhD

 

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

AKT_cClick on image to enlarge

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 Athe 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.

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.

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.

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.

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.

(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 BayerPhase 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 panAkt 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

1. Song G, Ouyang G, Bao S (2005) The activation of Akt/PKB signaling pathway and cell survival. J Cell Mol Med 9 (1):59-71

2. Gonzalez E, McGraw TE (2009) The Akt kinases: isoform specificity in metabolism and cancer. Cell Cycle 8 (16):2502-2508

3. Vivanco I, Sawyers CL (2002) The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer 2 (7):489-501

4. Altomare DA, Testa JR (2005) Perturbations of the AKT signaling pathway in human cancer. Oncogene 24 (50):7455-7464

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

6. Kim D, Dan HC, Park S, Yang L, Liu Q, Kaneko S, Ning J, He L, Yang H, Sun M, Nicosia SV, Cheng JQ (2005) AKT/PKB signaling mechanisms in cancer and chemoresistance. Front Biosci 10:975-987

7. Pal SK, Reckamp K, Yu H, Figlin RA (2010) Akt inhibitors in clinical development for the treatment of cancer. Expert Opin Investig Drugs 19 (11):1355-1366

8. Hsieh AC, Truitt ML, Ruggero D (2011) Oncogenic AKTivation of translation as a therapeutic target. Br J Cancer 105 (3):329-336

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

11. Weigelt B and Downward J (2012) Genomic Determinants of PI3K Pathway Inhibitor Response in Cancer. Front Oncol. 2012;2:109

12. Janna Elizabeth Hutz. Genetic analysis of the PI3k/AKT/mTOR signaling pathway. udini.proquest.com

Resources

New medicine Oncology KnowledgeBASE (nmOK)

ClinicalTrials.gov

Related articles on this Open Access Online Scientific Journal

AKT signaling variable effects. Reporter: Larry H Bernstein, MD

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CD47: Target Therapy for Cancer

Author/Curator: Tilda Barliya

“A research team from Stanford University’s School of Medicine is now one step closer to uncovering a cancer treatment that could be applicable across the board in killing every kind of cancer tumor” (1). It appeared that their antibody-drug against the CD47 protein, enabled the shrinking of all tumor cells. After completing their animal studies the researchers now move into a human phase clinical trials. CD47 has been previously studied and evaluated for its role in multiple cells, some of this data however, is somewhat controversy. So where do we stand?

CD47

CD47 (originally named integrin-associated protein (IAP)) is a cell surface protein of the immunoglobulin (Ig) superfamily, which is heavily glycosylated and expressed by virtually all cells in the body and overexpressed in many types of cancer  including breast, ovarian, colon, prostate and others (3). CD47 was first recognized as a 50 kDa protein associated and copurified with the  Alpha-v-Beta-3 integrin in placenta and neutrophil granulocytes and later shown to have the capacity to regulate integrin function and the responsiveness of leukocytes to RGD-containing extracellular matrix proteins. CD47 has also been shown to be identical to the OA-3/OVTL3 antigen highly expressed on most ovarian carcinomas (4,5).

CD47 consists of an extracellular IgV domain, a five times transmembrane-spanning domain, and a short alternatively spliced cytoplasmic tail. In both humans and mice, the cytoplasmic tail can be found as four different splice isoforms ranging from 4 to 36 amino acids, showing different tissue expression patterns (3).

CD47 interactions (3, 6):

  • Thrombospondin-1 (TSP-1) – a secreted glycoprotein that plays a role in vascular development and angiogenesis. Binding of TSP-1 to CD47 influences several fundamental cellular functions including cell migration and adhesion, cell proliferation or apoptosis, and plays a role in the regulation of angiogenesis and inflammation.
  • Signal-regulatory protein-alpha (SIRPα) – an inhibitory transmembrane receptor present on myeloid cells. The CD47/SIRPα interaction leads to bidirectional signaling, resulting in different cell-to-cell responses including inhibition of phagocytosis, stimulation of cell-cell fusion, and T-cell activation.
  • Integrins – several membrane integrins, most commonly integrin avb3. These interactions result in CD47/integrin complexes that effect a range of cell functions including adhesion, spreading and migration

These interactions with multiple proteins and cells types create several important functions, which include:

  • Cell proliferation – cell proliferation is heavily dependent on cell type as both activation and loss of CD47 can result in enhanced proliferation. For example, activation of CD47 with TSP-1 in wild-type cells inhibits proliferation and reduces expression of stem cell transcription factors. In cancer cells however, activation of CD47 with TSP-1 increases proliferation of human U87 and U373 astrocytoma. it is likely that CD47 promotes proliferation via the PI3K/Akt pathway in cancerous cells but not normal cells (7).  Loss of CD47 allows sustained proliferation of primary murine endothelial cells and enables these cells to spontaneously reprogram to form multipotent embryoid body-like clusters (8).
  • Apoptosis – Ligation of CD47 by anti-CD47 mAbs was found to induce apoptosis in a number of different cell types (3). For example: Of the two SIRP-family members known to bind the CD47 IgV domain (SIRPα and SIRPγ), SIRPα as a soluble Fc-fusion protein does not induce CD47-dependent apoptosis, hile SIRPα or SIRPγ bound onto the surface of beads induces apoptosis through CD47 in Jurkat T cells and the myelomonocytic cell line U937.
  • Migration – CD47  role on cell migration was first demonstrated in neutrophils, these effects were shown to be dependent on avb3 integrins, which interact with and are activated by CD47 at the plasma membrane. In cancer, Blocking CD47 function has been shown to inhibit migration and metastasis in a variety of tumor models. Blockade of CD47 by neutralizing antibodies reduced migration and chemotaxis in response to collagen IV in melanomaprostate cancer and ovarian cancer-derived cells (9).
  • Angiogenesis – The mechanism of the anti-angiogenic activity of CD47 is not fully understood, but introduction of CD47 antibodies and TSP-1 have been shown to inhibit nitric oxide (NO)-stimulated responses in both endothelial and vascular smooth muscle cells (10). More so, CD47 signaling influences the SDF-1 chemokine pathway, which plays a role in angiogenesis (11). (12)
  • Inflammatory response – Interactions between endothelial cell CD47 and leukocyte SIRPγ regulate T cell transendothelial migration (TEM) at sites of inflammation. CD47 also functions as a marker of self on murine red blood cells which allows RBC to avoid phagocytosis. Tumor cells can also evade macrophage phagocytosis through the expression of CD47 (2, 13).

It appears that CD47 ligation induce different responses, depending on cell type and partner for ligation.

Therapeutic and clinical aspect of CD47 in human cancer:

CD47 is overexpressed in many types of human cancers  and its known function as a “don’t eat me” signal, suggests the potential for targeting the CD47-SIRPα pathway as a common therapy for human malignancies (2,13). Upregulation of CD47 expression in human cancers also appears to influence tumor growth and dissemination. First, increased expression of CD47 in several hematologic malignancies was found to be associated with a worse clinical prognosis, and in ALL to predict refractoriness to standard chemotherapies (13, 14-16). Second, CD47 was demonstrated to regulate tumor metastasis and dissemination in both MM and NHL (13, 17).

Efforts have been made to develop therapies inhibiting the CD47-SIRPα pathway, principally through blocking monoclonal antibodies directed against CD47, but also possibly with a recombinant SIRPα protein that can also bind and block CD47.

Figure 2

Chao MP et al. 2012 Combination strategies targeting CD47 in cancer

While monotherapies targeting CD47 were efficacious in several pre-clinical tumor models, combination strategies involving inhibition of the CD47-SIRPα pathway offer even greater therapeutic potential. Specifically, antibodies targeting CD47-SIRPα can be included in combination therapies with other therapeutic antibodies, macrophage-enhancing agents, chemo-radiation therapy, or as an adjuvant therapy to inhibit metastasis (13).

For example, anti-SIRPα antibody was found to potentiate  antibody-dependent cellular cytotoxicity (ADCC) mediated by the anti-Her2/Neu antibody trastuzumab against breast cancer cells (18).  CD47–SIRPα interactions and SIRPα signaling negatively regulate trastuzumab-mediated ADCC in vitro and antibody-dependent elimination of tumor cells in vivo

More so, chemo-radiation therapy-mediated upregulation of cell surface calreticulin may potentially augment the activity of anti-CD47 antibody. However, this approach may also lead to increased toxicity as cell surface calreticulin is expressed on non-cancerous cells undergoing apoptosis, a principle effect of chemo-radiation therapy (19).

Highlights:

  • Phagocytic cells, macrophages, regulate tumor growth through phagocytic clearance
  • CD47 binds SIRPα on phagocytes which delivers an inhibitory signal for phagocytosis
  • A blocking anti-CD47 antibody enabled phagocytic clearance of many human cancers
  • Phagocytosis depends on a balance of anti-(CD47) and pro-(calreticulin) signals
  • Anti-CD47 antibody synergized with an FcR-engaging antibody, such as rituximab

Summary

Evasion of immune recognition is a major mechanism by which cancers establish and propagate disease. Recent data has demonstrated that the innate immune system plays a key role in modulating tumor phagocytosis through the CD47-SIRPα pathway. Careful development of reagents that can block the CD47/SIRPα interaction may indeed be useful to treat many forms of cancer without having too much of a negative side effect in terms of inducing clearance of host cells. Therapeutic approaches inhibiting this pathway have demonstrated significant efficacy, leading to the reduction and elimination of multiple tumor types.

Dr. Weissman says: “We are now hopeful that the first human clinical trials of anti-CD47 antibody will take place at Stanford in mid-2014, if all goes wellClinical trials may also be done in the United Kingdom”. These clinical trials must be designed so that the data they generate will produce a valid scientific result!!!

REFERENCES

1. By Sara Gates:  Cancer Drug That Shrinks All Tumors Set To Begin Human Clinical Trials. http://www.huffingtonpost.com/2013/03/28/cancer-drug-shrinks-tumors_n_2972708.html

2. Willingham SB, Volkmer JP, Gentles AJ, Sahoo D, Dalerba P, Mitra SS, Wang J, Contreras-Trujillo H, Martin R, Cohen JD, Lovelace P, Scheeren FA, Chao MP, Weiskopf K, Tang C, Volkmer AK, Naik TJ, Storm TA, Mosley AR, Edris B, Schmid SM, Sun CK, Chua MS, Murillo O, Rajendran P, Cha AC, Chin RK, Kim D, Adorno M, Raveh T, Tseng D, Jaiswal S, Enger PØ, Steinberg GK, Li G, So SK, Majeti R, Harsh GR, van de Rijn M, Teng NN, Sunwoo JB, Alizadeh AA, Clarke MF, Weissman IL. The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors. Proc Natl Acad Sci U S A. 2012 Apr 24;109(17):6662-6667. http://www.pnas.org/content/early/2012/03/20/1121623109

3. Oldenborg PL. CD47: A Cell Surface Glycoprotein Which Regulates Multiple Functions of Hematopoietic Cells in Health and Disease. ISRN Hematology Volume 2013 (2013), Article ID 614619, 19 pages.  http://www.hindawi.com/isrn/hematology/2013/614619/

4. G. Campbell, P. S. Freemont, W. Foulkes, and J. Trowsdale, “An ovarian tumor marker with homology to vaccinia virus contains an IgV- like region and multiple transmembrane domains,”Cancer Research, vol. 52, no. 19, pp. 5416–5420, 1992. http://cancerres.aacrjournals.org/content/52/19/5416.long

5. L. G. Poels, D. Peters, Y. van Megen et al., “Monoclonal antibody against human ovarian tumor-associated antigens,” Journal of the National Cancer Institute, vol. 76, no. 5, pp. 781–791, 1986. http://www.ncbi.nlm.nih.gov/pubmed/3517452

6. CD47. Wikipedia. http://en.wikipedia.org/wiki/CD47

7. Sick E, Boukhari A, Deramaudt T, Rondé P, Bucher B, André P, Gies JP, Takeda K (February 2011). “Activation of CD47 receptors causes proliferation of human astrocytoma but not normal astrocytes via an Akt-dependent pathway”. Glia 59 (2): 308–319. http://www.ncbi.nlm.nih.gov/pubmed/21125662

8. Kaur S, Soto-Pantoja DR, Stein EV, Liu C, Elkahloun AG, Pendrak ML, Nicolae A, Singh SP, Nie Z, Levens D, Isenberg JS, Roberts DD.  “Thrombospondin-1 Signaling through CD47 Inhibits Self-renewal by Regulating c-Myc and Other Stem Cell Transcription Factors”Sci Rep 2013: 3: 1673. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3628113/

9. Shahan TA, Fawzi A, Bellon G, Monboisse JC, Kefalides NA. “Regulation of tumor cell chemotaxis by type IV collagen is mediated by a Ca(2+)-dependent mechanism requiring CD47 and the integrin alpha(V)beta(3)”. J. Biol. Chem 2000. 275 (7): 4796–4802. http://www.jbc.org/content/275/7/4796

10. Isenberg JS, Ridnour LA, Dimitry J, Frazier WA, Wink DA, Roberts DD. “CD47 is necessary for inhibition of nitric oxide-stimulated vascular cell responses by thrombospondin-1”. J. Biol. Chem  2006. 281 (36): 26069–26080.  http://www.jbc.org/content/281/36/26069

11. Smadja DM, d’Audigier C, Bièche I, Evrard S, Mauge L, Dias JV, Labreuche J, Laurendeau I, Marsac B, Dizier B, Wagner-Ballon O, Boisson-Vidal C, Morandi V, Duong-Van-Huyen JP, Bruneval P, Dignat-George F, Emmerich J, Gaussem P. “Thrombospondin-1 is a plasmatic marker of peripheral arterial disease that modulates endothelial progenitor cell angiogenic properties”. Arterioscler. Thromb. Vasc. Biol  2011. 31 (3): 551–559. http://atvb.ahajournals.org/content/31/3/551

12. G. D. Grossfeld, D. A. Ginsberg, J. P. Stein et al., “Thrombospondin-1 expression in bladder cancer: association with p53 alterations, tumor angiogenesis, and tumor progression,” Journal of the National Cancer Institute 1997 vol. 89, no. 3, pp. 219–227. http://www.scopus.com/record/display.url?eid=2-s2.0-18744423089&origin=inward&txGid=9C86356DDB0B6816ACCBF90F9CA44E92.WlW7NKKC52nnQNxjqAQrlA%3a2

13. Chao MP, Weissman IL, Majeti R. “The CD47-SIRPα pathway in cancer immune evasion and potential therapeutic implications”Curr. Opin. Immunol 2012. 24 (2): 225–32. http://www.sciencedirect.com/science/article/pii/S095279151200012Xhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3319521/

14. Majeti R, Chao MP, Alizadeh AA, Pang WW, Jaiswal S, Gibbs KD, Jr, van Rooijen N, Weissman IL. Cd47 is an adverse prognostic factor and therapeutic antibody target on human acute myeloid leukemia stem cells. Cell. 2009;138(2):286–299. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2726837/

15. Chao MP, Alizadeh AA, Tang C, Jan M, Weissman-Tsukamoto R, Zhao F, Park CY, Weissman IL, Majeti R. Therapeutic antibody targeting of cd47 eliminates human acute lymphoblastic leukemia.Cancer Res. 2011;71 (4):1374–1384. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3041855/

16. Chao MP, Alizadeh AA, Tang C, Myklebust JH, Varghese B, Gill S, Jan M, Cha AC, Chan CK, Tan BT, Park CY, et al. Anti-cd47 antibody synergizes with rituximab to promote phagocytosis and eradicate non-hodgkin lymphoma. Cell. 2010;142(5):699–713. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2943345/

17. Chao MP, Tang C, Pachynski RK, Chin R, Majeti R, Weissman IL. Extranodal dissemination of non-hodgkin lymphoma requires cd47 and is inhibited by anti-cd47 antibody therapy. Blood.2011;118(18):4890–4901. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3208297/

18. Zhao XW, van Beek EM, Schornagel K, Van der Maaden H, Van Houdt M, Otten MA, Finetti P, Van Egmond M, Matozaki T, Kraal G, Birnbaum D, et al. Cd47-signal regulatory protein-alpha (sirpalpha) interactions form a barrier for antibody-mediated tumor cell destruction. Proc Natl Acad Sci U S A.2011;108(45):18342–18347. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3215076/

19. Obeid M, Tesniere A, Ghiringhelli F, Fimia GM, Apetoh L, Perfettini JL, Castedo M, Mignot G, Panaretakis T, Casares N, Metivier D, et al. Calreticulin exposure dictates the immunogenicity of cancer cell death. Nat Med. 2007;13(1):54–61. http://www.ncbi.nlm.nih.gov/pubmed/17187072

Other related articles on this Open Access Online Scientific Journal include the following:

I. By: Larry Bernstein MD. Treatment for Metastatic HER2 Breast Cancer https://pharmaceuticalintelligence.com/2013/03/03/treatment-for-metastatic-her2-breast-cancer/

II. By: Tilda Barliya PhD. Colon Cancer.  https://pharmaceuticalintelligence.com/2013/04/30/colon-cancer/

III. By: Ritu Saxena PhD. In focus: Triple Negative Breast Cancer. https://pharmaceuticalintelligence.com/2013/01/29/in-focus-triple-negative-breast-cancer/

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