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Posts Tagged ‘Chemokine’


Are CXCR4 Antagonists Making a Comeback in Cancer Chemotherapy?

Reporter: Stephen J. Williams, Ph.D.

Biospace News reported that Massachusetts based X4 Pharmaceuticals is using $34B to launch two clinical trials on its CXCR4 inhibitor X4P-001 in refractory clear cell renal cell carcinoma and refractory epithelial ovarian cancer.

The full report is below:

X4 Pharma Uses $37.5 Million to Push Cancer Therapies into Human Trials

 

December 14, 2015
By Alex Keown, BioSpace.com Breaking News Staff

CAMBRIDGE, Mass. – Massachusetts based X4 Pharmaceuticals is beginning human trials for its oncology program using CXCR4 inhibitors, the Boston Business Journal reported this morning.

After spending years in stealth mode, the company, helmed by former Genzyme executives, is launching two clinical two clinical studies initiating in 2016 in refractory clear cell renal cell carcinoma and refractory epithelial ovarian cancer with its lead drug candidate, X4P-001.

The company’s pipeline is based on drug compounds that originate from a portfolio of oral CXCR4 inhibitors exclusively licensed from Sanofi (SNY), X4 said in a statement. Inhibition of CXCR4, a receptor over-expressed in many cancers, is designed to block non-cancerous immuno-suppressive and pro-angiogenic cells from populating the tumor, thereby disrupting the cancer microenvironment and restoring normal immune surveillance functions. The novel mechanism of CXCR4 inhibition increases the ability of T-Cells to track and destroy cancer. X4 is leveraging its CXCR4 research against past experience working with Genzyme’s plerixafor, which is also a CXCR4 blocker.

In an interview with the Journal, Paula Ragan, X4’s chief executive officer, said the CXCR4 protein “acts as a beacon to attract cells to surround a tumor, effectively hiding the tumor from the body’s T cells that would otherwise destroy them.” Developing a therapy to block the protein will prevent the tumors from hiding and allow it to be treated.

Ragan said the Phase Ia trial for X4P-001 will test safety and dosage in a small trial of about 20 people, the Journal reported. If all goes well the company would start a Phase 2a trial by the end of 2016 in around 50 or 60 patients, the Journal said.

In September, Ragan said a CXCR4 antagonist could potentially be paired with promising oncology drugs like Merck & Co. (MRK)’s Keytruda, or Bristol-Myers Squibb (BMY)’s Opdivo. Keytruda has been shown to be effective in treating patients with three types of cancer, melanoma, lung cancer and mesothelioma. Opdivo is a treatment of patients with metastatic squamous non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy.

The cytokines and cytokine receptors have been investigated before for their utility as a chemotherapeutic target as they are highly expressed on tumors and promote metastasis. The general idea was that tumor cells secrete cytokines which promote their growth and metastases and attract immune cells which also secrete growth-promoting cytokines. Many tumor types have shown increased expression of these cytokines and cytokine receptors. However only some development efforts have shown promise, there have been no approved drugs in this class. As written in a previous post (Tumor Associated Macrophages: The Double-Edged Sword Resolved?), there could be many biological reasons for this, as well as difficulties in interpreting preclinical results in immunocompromised mice.

CXCR4: from the review by Ori Wald, Oz M. Shapira, Uzi Izha

 

Source: Wald O, Shapira OM, Izhar U. CXCR4/CXCL12 Axis in Non Small Cell Lung Cancer (NSCLC) Pathologic Roles and Therapeutic Potential. Theranostics 2013; 3(1):26-33. doi:10.7150/thno.4922. Available from http://www.thno.org/v03p0026.htm

 

Chemokines, a family of 48 chemotactic cytokines interact with their 7 transmembrane G-protein-coupled receptors to guide immune cell trafficking in the body under both physiologic and pathologic conditions (20, 21). Tumor cells, which express a relatively restricted repertoire of chemokine and chemokine receptors, utilize and manipulate the chemokine system in a manner that benefits both local tumor growth and distant dissemination (20, 22, 23). In the tumor microenvironment autocrine and paracrine chamokine/chemokine receptor loops interact to promote tumor cell survival and growth, and also to enhance tumor neo-angiogenesis (20, 22, 23). At distant sites, it is the tissue-produced chemokine which guide/attracts the metastasis of chemokine receptor expressing tumor cells (20).

Among the 19 chemokine receptors, CXCR4 is the receptor most widely expressed by malignant tumors and whose role in tumor biology is most thoroughly studied (20). The chemokine CXCL12 is the sole ligand of CXCR4 and the majority of research that focus on the role of CXCR4 in cancer relates to this chemokine/chemokine receptor pair (24, 25). Nevertheless, in 2006 another receptor for CXCL12 was identified and named CXCR7 (26). CXCR7 is expressed during embriogenesis, angiogenesis and in various malignant tissues including NSCLC. CXCR7 is thought to act in part as a scavenger of CXCL12 however additional functions for this receptor have also been reported (2628). In distinct form CXCR4, CXCR7 binds not only CXCL12 but also the chemokine CXCL11 (26, 27). Moreover, the signaling cascades that are generated upon binding of CXCL12 to CXCR4 or CXCR7 vary at least partly, depending on which of the receptors is engaged (26, 27). This review focuses mainly on data collected regarding the expression and function of CXCR4 in NSCLC, nevertheless it is important to keep in mind that whenever CXCL12 is mentioned the effects related to its expression may be attributed in part to CXCR7 expression and function.

Relative to normal cells in the tumor’s tissue of origin, malignant cells often over express CXCR4, this phenotype can be induced by multiple oncogenic alternations and appears to promote tumor cell survival, proliferation, invasion and metastasis (20, 2935).

 

 

 

cxcrimagetumorncls

Potential roles for CXCR4/CXCL12 in NSCLC. NSCLC tumor cells express CXCR4 and produce CXCL12. Tumor expressed CXCR4 guides metastatic spread to sights such as the brain, bone marrow and liver that express high levels of CXCL12. In addition, CXCR4/CXCL12 interactions act locally in autocrine and paracrine manners to enhance primary tumor growth and to alter its inflammatory milieu. Tumor and tumor microenvironment secreted CXCL12 enhance tumor cell survival and growth and may also guide trafficking of immune and bone marrow derived cells into the tumor microenvironment. Furthermore, alternations in the tumor microenvironment result from the stimulation of tumor cells with CXCL12 that in turn enhance the production of additional chemokines such as the pro-inflammatory and pro-proliferative chemokine CCL20) pro-angiogenic and pro-proliferative chemokine (CXCL1 – IL-8). Figure from Wald O, Shapira OM, Izhar U. CXCR4/CXCL12 Axis in Non Small Cell Lung Cancer (NSCLC) Pathologic Roles and Therapeutic Potential. Theranostics 2013; 3(1):26-33. doi:10.7150/thno.4922. Available from http://www.thno.org/v03p0026.htm

For further reference on CXCR4 and development of CXCR4 inhibitors please see the following references:

  1. Peled A, Wald O, Burger J. Development of novel CXCR4-based therapeutics. Expert Opin Investig Drugs. 2012Mar;21(3):341-53
  2. Balkwill FR. The chemokine system and cancer. J Pathol. 2012Jan;226(2):148-57
  3. Burger JA, Kipps TJ. CXCR4: a key receptor in the crosstalk between tumor cells and their microenvironment. Blood. 2006Mar1;107(5):1761-7
  4. Burger JA, Peled A. CXCR4 antagonists: targeting the microenvironment in leukemia and other cancers. Leukemia. 2009Jan;23(1):43-52
  5. Otsuka S, Bebb G. The CXCR4/SDF-1 chemokine receptor axis: a new target therapeutic for non-small cell lung cancer. J Thorac Oncol. 2008Dec;3(12):1379-83

 

Current CXCR4 inhibitors in development

somecxcr4inhibitors

Figure. Structures of Representative Small Molecule CXCR4 Antagonists and CXCL12 Inhibitors. From JJ Zariek et al. Fragment-Based Optimization of Small Molecule CXCL12 Inhibitors for Antagonizing the CXCL12/CXCR4 Interaction. Curr Top Med Chem. 2012; 12(24): 2727–2740.

 

A Phase 1 Trial of LY2510924, a CXCR4 Peptide Antagonist, in Patients with Advanced Cancer

This manuscript reports the results of a phase I study designed to evaluate the safety and tolerability of the C-X-C motif receptor 4 (CXCR4) inhibitor LY2510924 in patients with advanced cancer. LY2510924 is a peptide antagonist, which blocks stromal cell-derived factor-1 (SDF-1) from CXCR4 binding. CXCR4 is often overexpressed in many cancers and involved in the metastasis of solid tumors. LY2510924 was tolerated with mostly Grade 1/2 adverse events, revealed favorable pharmacokinetics, and demonstrated evidence of target engagement as indicated by dose dependent increases in CD34+ cells.

Anti-CXCR4 (BMS-936564) Alone and in Combination With Lenalidomide/Dexamethasone or Bortezomib/Dexamethasone in Relapsed/Refractory Multiple Myeloma

The purpose of this study is to determine 1) the safety and tolerability of multiple intravenous doses of anti-CXCR4 (BMS-936564) as monotherapy and as combination, and 2) the maximum tolerated dose (MTD) of BMS-936564 in combination with Lenalidomide/Dexamethasone or Bortezomib/Dexamethasone in subjects with relapsed or refractory multiple myeloma.

 

Novel CXCR4 Antagonist BL-8040 Enters Clinical Testing for CML – See more at: http://www.cancernetwork.com/chronic-myeloid-leukemia/novel-cxcr4-antagonist-enters-clinical-testing-cml#sthash.RoXCC5W6.dpuf

 

Other posts on this Open Access Journal on CXCR4 and Chemokines in Cancer Include

Assessing effects of antimetastatic treatment

Understanding the Stem Cell Niche: A Webinar by The Scientist

Protein regulator of HIV replication

Immunotherapy in Cancer: A Series of Twelve Articles in the Frontier of Oncology by Larry H Bernstein, MD, FCAP

Humanized Mice May Revolutionize Cancer Drug Discovery

Tumor Associated Macrophages: The Double-Edged Sword Resolved?

 

 

 

 

 

 

 

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Approach to Controlling Pathogenic Inflammation in Arthritis

Curator: Larry H Bernstein, MD, FCAP

A network approach to controlling pathogenic inflammation: Sequence sharing pattern peptides downregulate experimental arthritis

a new approach to network regulation of inflammation based on

Chai Ezerzer, Raanan Margalit and Irun R. Cohen

Aberrant inflammation probably results from aberrant regulation of the molecules that mediate inflammation; the actual molecules mediating inflammation –

  • chemokines,
  • cytokines, and
  • growth factors and their receptors –
    • would appear to be normal in their chemical structure.

If faulty regulation is indeed the problem,

  • a reasonable approach to alleviating inflammatory diseases might be to influence the interactions
  • within the network of connectivity of the disease-associated proteins (DAPs).
Aberrant inflammation appears to be a pathogenic factor in autoimmune diseases and other noxious inflammatory
conditions in which the inflammatory process
  1. is misapplied,
  2. exaggerated,
  3. recurrent or chronic.
The protein molecules involved in pathogenic inflammation—
disease-associated proteins (DAP )
  1. chemokines,
  2. cytokines, and
  3. growth factors and their receptors,
  • appear normal; their networks of interaction are at fault.

These researchers asked the question – 

  • whether shared amino acid sequence motifs among DAPs
  • might identify novel peptide treatments for regulating inflammation.

We aligned the sequences of 37 DAPs previously discovered to be associated with arthritis

  • to uncover shared sequence motifs.

We focused on chemokine receptor molecules because

  • chemokines and chemokine receptors play important roles in directing the migration of inflammatory cells into sites of tissue inflammation.
  •  different chemokine receptors shared amino acid sequence motifs in their extra-cellular loop domains (ECL2);
  • the ECL2 loop is outside of the known ligand binding site.

These shared sequence motifs established what we term a sequence-sharing network (SSN). SSN motifs exhibited very low E-values,

  • indicating their preservation during evolution.
This study demonstrates a new
  • approach to network regulation of inflammation based on peptide sequence motifs
  • shared by the second extra-cellular loop (EC L2) of different chemokine receptors;
  • previously known chemokine receptor binding sites have not involved the EC L2 loop.
These motifs of 9 amino acids, which were detected by sequence alignment, manifest very low E-values
  • compared with slightly modified sequence variations,
  • indicating that they were not likely to have evolved by chance.
To test whether this shared sequence network (SSN) might serve a regulatory function,
  • theysynthesized 9-amino acid SSN peptides from the EC L2 loops of three different chemokine receptors.
Theye administered these peptides to rats during the
Two of the peptides significantly downregulated the arthritis; one of the peptides
  • synergized with non-specific anti-inflammatory treatment with dexamethasone.
These findings suggest that
  • the SSN peptide motif reported here is likely to have adaptive value in controlling inflammation.
  • detection of SSN motif peptides could provide a network-based approach to immune modulation.
administering a highly connected chemokine receptor peptide motif , as done here, induced
  • the downregulation of inflammation in a rat model of arthritis.
Thus, study of the SSN provides a new network approach toward modulating inflammation
English: Typical chemokine receptor structure ...

English: Typical chemokine receptor structure showing seven transmembrane domains and a chanracteristic “DRY” motif in the second intracelluar domain. (Photo credit: Wikipedia)

Structure of Chemokines

Structure of Chemokines (Photo credit: Wikipedia)

Chemokine receptor

Chemokine receptor (Photo credit: Wikipedia)

 

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