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Combining Nanotube Technology and Genetically Engineered Antibodies to Detect Prostate Cancer Biomarkers

Posted in Bio Instrumentation in Experimental Life Sciences Research, Biomarkers & Medical Diagnostics, BioSimilars, CANCER BIOLOGY & Innovations in Cancer Therapy, Cancer Prevention: Research & Programs, Disease Biology, Small Molecules in Development of Therapeutic Drugs, FDA Regulatory Affairs, Health Economics and Outcomes Research, Human Immune System in Health and in Disease, Interviews with Scientific Leaders, ISO 10993 for Product Registration: FDA & CE Mark for Development of Medical Devices and Diagnostics, Medical Devices R&D Investment, tagged Antibody, bioengineering, Biosensors, breast cancer, Cancer - General, health, HER2, nanotechnology, osteopontin, Prostate cancer, Trastuzumab on June 13, 2013| 4 Comments »

Combining Nanotube Technology and Genetically Engineered Antibodies to Detect Prostate Cancer Biomarkers

Writer, Curator: Stephen J. Williams, Ph.D.

WordCloud Image Produced by Adam Tubman

Figure of  Carbon Nanotube Transistor design with functionalized antibodies for biomarker detection.  From paper of A.T. Johnson; used with permission from A.T. Johnson)

In a literature review of the current status of the breast cancer biomarker field[2], author Dr. Michael Duffy, from University College Dublin, pondered the clinical utility of breast cancer serum markers and suggested that due to lack of sensitivity and specificity none of available markers is of value for detection of early breast cancer however these biomarkers have been shown useful in monitoring patients with advanced disease. For instance high preoperative CA15-3 is indicative of adverse patient outcome.  According to American Society of Clinical Oncology Expert Panel, however CA 15-3 may lack the sensitivity and disease specificity for breast cancer as a prognostic marker.  For panel suggestions please click on the link below:

http://www.asco.org/sites/www.asco.org/files/breast_tm_2007_changes-final.pdf

The same panel also concurred on the lack of prognostic value of other markers (for example CEA for colon cancer) but did agree that 66-73% of patients with advanced disease, who responded to therapy, showed reduction in these serum markers.  Indeed, CA125, long associated as a biomarker for ovarian cancer, does not have the sensitivity and especially the disease specificity to be a stand-alone prognostic marker[3].  Therefore, although “omics” strategies have suggested multiple possible biomarkers  for various cancers, a major issue in translating a putative biomarker to either:

1)      a clinically validated (panel) of disease-relevant biomarkers or

2)      biomarkers useful for therapeutic monitoring

is obtaining the specificity and sensitivity for detection in bio-specimens.   As discussed below, this is being achieved with the merger of nanotechnology-based sensors and bioengineering of biomolecule.

For ASCO panel suggestions of biomarkers useful in Prostate cancer please see the link below:

http://jco.ascopubs.org/site/misc/specialarticles.xhtml#GENITOURINARY_CANCER

As a side note, since 2010, ASCO has focused on reviewing and producing new guidelines for cancer biomarkers including genome sequencing:

http://www.medscape.com/viewarticle/723349

Osteopontin (OPN) and prostate cancer

Osteopontin is a phosphorylated glycoprotein secreted by activated macrophages, leukocytes, activated T lymphocytes and is present at sites of inflammation (for a review of OPN see [4]).  Osteopontin interacts with several integrins and CD44 (a putative cancer stem cell marker).  Binding of OPN to cell integrins mediates cell-matrix and cell-cell communication, stimulating adhesion, migration (through interaction with urokinase plasminogen activator {uPA}) and cell signaling pathways such as the HGF-Met pathway.  Overexpression is found on a variety of cancers including breast, lung, colorectal, ovarian and melanoma[5].  And although OPN is detected in normal tissue, it is known that OPN over-expression can alter the malignant potential of tumor cells.

Roles of osteopontin in cancer include:

• Binding to CD44
• Increase in growth factor signaling (HGF/Met pathway)
• Increase uPA activity- increase invasiveness
• Angiogenesis thru binding with α_vβ₃ integrin and increased VEGF expression
• Protection against apoptosis: OPN activates nuclear factor Κβ

Some researchers have suggested it could be a prognostic marker for breast and lung cancer while there have been conflicting reports as to whether OPN expression is correlated to malignant potential in prostate cancer[6].  Osteopontin is found on tumor infiltrating macrophages, which may contribute to OPN as a prognostic marker. Breast cancer patients (disseminated carcinomas) have 4-10 times higher serum levels of OPN than found in healthy patients, although there is no difference in pre- or post-menopausal women[7].

Piezoelectric sensors have been used by the same group at Fox Chase Cancer Center to detect serum levels of the HER2 protein in breast cancer patients, for the purpose of therapeutic monitoring after anti-HER2 antibody trastuzumab (Herceptin™) therapy.  Lina Loo, in the laboratory of Dr. Gregory Adams showed the utility of using (scFv) to trastuzumab (anti-HER2) with pizo-electric nanotubes to accurately and reproducibly determine levels of serum HER2[8].  This method improved the sensitivity of serum HER2 detection over other methods such as:

• ELISA {enzyme-linked immunoassay}
• Luminex platforms

Please watch the following video interview concerning genetically engineered scFV antibody fragments and their use in cancer detection and treatment (with Dr. Matt Robinson and Dr. Greg Adams, from Fox Chase Cancer Center)

PLEASE WATCH VIDEO

However the advent of nanotechnology-based detection system combined with engineered affinity-based biomolecules has increased both the sensitivity and specificity of biomarker detection from complex fluids such as plasma and urine.  The advent of multiple types of biosensors, including

has given the ability to measure, with enhanced sensitivity and specificity,  putative biomarkers of disease in minute volumes of precious bio-samples.

The basic design of a biosensor is made of three components:

1. A recognition element (I.e. antibodies, nucleic acids, enzymes)
2. A signal transducer (electrochemical, optical, piezoelectric)
3. Signal processor (relays and displays)

In the journal ACS Nano Mitchel Lerner from Dr. Charlie Johnson’s laboratory at University of Pennsylvania in collaboration with Fox Chase Cancer researchers in the laboratory of Dr. Matthew Robinson, describe a piezoelectric detection system for quantifying levels of osteopontin (OPN), a putative biomarker for prostate cancer[1].  In this paper Dr. Robinson’s group at Fox Chase, genetically engineered a single chain variable fragment (scFv) protein {the binding portion of the antibody} which had high affinity for OPN.  This scFv was attached to a carbon nanotube field-effect transistor (NT-FET), designed by Dr. Johnson’s group, using a chemical process called chemical functionalization {a process using diazonium salts to covalently attach scFV to NT-FET.

Figure. Functionalization scheme for OPN attachment to carbon nanotubes. As figure 1 legend in paper states: “First, sp8 hybridized-sites are created o the nanotube sidewall by incubation in a diazonium salt solution.  The carboxylic acid group is then activated by EDC and stabilized with NHS.ScFv antibody displaces the NHS and forms an amide bond.  OPN epitope is shown in yellow and the C and N-terminuses are in orange and green respectively.” (used by permision for A.T. Charlie Johnson)

This system was then used to determine the selectivity and sensitivity of OPN from complex solutions.

Methods: 

Nanotube (NT) design

• Grown by catalytic vapor deposition
• Electrical contacts patterned using photo-lithography
• Atomic Force microscopy was used to verify structure of nanotube

Chemical Linking of scFv to nanotube

• Diazonium treatment resulted in activation and subsequent stabilization of amino (NHS) side chain
• Amine group on lysine of scFV displaced NHS group => covalent attachment of scFV to NT
• Atomic Force Spectroscopy used to verify linkage of scFv to nanotube

Results showed there was

• minimal non-specific binding of OPN to the scFv
• system allowed for detection limit of 1 pg/ml OPN (pictogram/milliliter) or 30 fM (fentomolar) in a phosphate buffered saline solution.
•  Only a minute volume (10 µl) of sample is needed
• Sensor able to measure million-fold  range of OPN concentrations ( from 10^-3 to 10³ ng/mL OPN)

Two experiments were conducted to determine the specificity of OPN to the antibody-detection system.

1^st experiment

–          scFv functionalized  sensor was incubated in a solution of high concentration of BSA (450 mg/ml) to approximate nonspecific proteins in patient samples

–           minimal signal was detected

        2^nd experiment

–          Functionalized NT-FET devices with a scFv based on the HER2 therapeutic antibody trastuzumab

–          There was no binding of OPN to anti-HER2 devices

–          Therefore anti OPN (23C3) scFv-functionalized carbon nanotube sensors exhibit high levels of specificity to OPN

The authors conclude “the functionalization procedure described here is expected to be generalizable to any antibody containing an accessible amine group, and to result in biosensors appropriate for detection of corresponding complementary proteins at fM concentrations”.

I had the opportunity to speak with co-author Dr. Matthew Robinson, Assistant Professor in the Developmental Therapeutics Program at Fox Chase Cancer Center about the next steps for this work.  Dr. Robinson mentioned that “at this point we have not looked in patient samples yet but our plan is to move in that direction. We need to establish sensitivity/specificity in increasingly complex samples (e.g. spiked normal serum and retrospectively in patient serum with known levels of biomarkers).” 

Cancer patients often present a complex metabolic profile.  The paper notes that OPN has a pI (isoelectric point) of 4.2, which would result in a negative charge at physiologically normal pH of 7.6. I asked Dr. Robinson about if changes in metabolic profile could hinder OPN binding to the NT-FET system would require some preprocessing of blood samples.  Dr. Robinson  agreed “that confounding variables such as additional diseases but even things like diet (i.e. is fasting necessary) need to be addressed before this platform is ready for use in clinical setting.
It is likely that sample prep will be needed to remove albumin, lower salt concentrations, etc. This could end up being problematic for biomarkers that are unstable and would degrade over the time necessary for sample prep. It is also possible that sample prep to remove albumin and other background factors could result in loss of biomarkers. This will need to be determined on a case-by-case basis with validated testing methods.”
One useful advantage of this system is the possibility of measuring multiple biomarkers, clinically important as studies has suggested that

multiple markers result in the higher sensitivity/specificity for many infrequent cancers, such as ovarian. Dr. Robinson agrees “that panels of biomarkers are likely to be better at early detection and diagnosis. In principle the platform that we describe can be set up to allow for detection of  multiple biomarkers at a time. From the biology end of things we have built antibodies against 3 different prostate cancer biomarkers for that purpose.”

Dr. Johnson  commented on the ability of the platform allowed for the simultaneous detection of multiple biomarkers, noting that ”the platform is compatible with the measurement of multiple biomarkers through the use of multiple devices, each functionalized with their own antibody.”

ASCO guidelines Expert Panel on Tumor Biomarkers 2007 Update for Breast Cancer:

http://www.asco.org/sites/www.asco.org/files/breast_tm_2007_changes-final.pdf 

ASCO Guidelines for Genitourinary Cancer:

Screening for Prostate Cancer With Prostate-Specific Antigen Testing: American Society of Clinical Oncology Provisional Clinical Opinion

Published in JCO, Vol. 30, Issue 24 (August 20), 2012: 3020-3025

American Society of Clinical Oncology Clinical Practice Guideline on Uses of Serum Tumor Markers in Adult Males With Germ Cell Tumors

Published in JCO, Vol 28, Issue 20 (July 10), 2010: 3388-3404

American Society of Clinical Oncology Endorsement of the Cancer Care Ontario Practice Guideline on Nonhormonal Therapy for Men With Metastatic Hormone-Refractory (castration-resistant) Prostate Cancer

Published in JCO, Vol 25, Issue 33 (November 20), 2007: 5313-5318

Initial Hormonal Management of Androgen-Sensitive Metastatic, Recurrent, or Progressive Prostate Cancer: 2006 Update of an American Society of Clinical Oncology Practice Guideline

Published in JCO, Vol. 25, Issue 12 (April 20), 2007: 1596-1605

References:

1.            Lerner MB, D’Souza J, Pazina T, Dailey J, Goldsmith BR, Robinson MK, Johnson AT: Hybrids of a genetically engineered antibody and a carbon nanotube transistor for detection of prostate cancer biomarkers. ACS nano 2012, 6(6):5143-5149.

2.            Duffy MJ: Serum tumor markers in breast cancer: are they of clinical value? Clinical chemistry 2006, 52(3):345-351.

3.            Meyer T, Rustin GJ: Role of tumour markers in monitoring epithelial ovarian cancer. British journal of cancer 2000, 82(9):1535-1538.

4.            Rodrigues LR, Teixeira JA, Schmitt FL, Paulsson M, Lindmark-Mansson H: The role of osteopontin in tumor progression and metastasis in breast cancer. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 2007, 16(6):1087-1097.

5.            Brown LF, Berse B, Van de Water L, Papadopoulos-Sergiou A, Perruzzi CA, Manseau EJ, Dvorak HF, Senger DR: Expression and distribution of osteopontin in human tissues: widespread association with luminal epithelial surfaces. Molecular biology of the cell 1992, 3(10):1169-1180.

6.            Thoms JW, Dal Pra A, Anborgh PH, Christensen E, Fleshner N, Menard C, Chadwick K, Milosevic M, Catton C, Pintilie M et al: Plasma osteopontin as a biomarker of prostate cancer aggression: relationship to risk category and treatment response. British journal of cancer 2012, 107(5):840-846.

7.            Brown LF, Papadopoulos-Sergiou A, Berse B, Manseau EJ, Tognazzi K, Perruzzi CA, Dvorak HF, Senger DR: Osteopontin expression and distribution in human carcinomas. The American journal of pathology 1994, 145(3):610-623.

8.            Loo L, Capobianco JA, Wu W, Gao X, Shih WY, Shih WH, Pourrezaei K, Robinson MK, Adams GP: Highly sensitive detection of HER2 extracellular domain in the serum of breast cancer patients by piezoelectric microcantilevers. Analytical chemistry 2011, 83(9):3392-3397.

Other posts from this site on Biomarkers, Cancer, and Nanotechnology include:

Stanniocalcin: A Cancer Biomarker.

Mesothelin: An early detection biomarker for cancer (By Jack Andraka)

Squeezing Ovarian Cancer Cells to Predict Metastatic Potential: Cell Stiffness as Possible Biomarker

PIK3CA mutation in Colorectal Cancer may serve as a Predictive Molecular Biomarker for adjuvant Aspirin therapy

Biomarker tool development for Early Diagnosis of Pancreatic Cancer: Van Andel Institute and Emory University

Early Biomarker for Pancreatic Cancer Identified

In Search of Clarity on Prostate Cancer Screening, Post-Surgical Followup, and Prediction of Long Term Remission

Prostate Cancer Molecular Diagnostic Market – the Players are: SRI Int’l, Genomic Health w/Cleveland Clinic, Myriad Genetics w/UCSF, GenomeDx and BioTheranostics

Early Detection of Prostate Cancer: American Urological Association (AUA) Guideline

A Blood Test to Identify Aggressive Prostate Cancer: a Discovery @ SRI International, Menlo Park, CA

Prostate Cancer Cells: Histone Deacetylase Inhibitors Induce Epithelial-to-Mesenchymal Transition

Prostate Cancer and Nanotecnology

 

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CD47: Target Therapy for Cancer

Posted in Advanced Drug Manufacturing Technology, Biomarkers & Medical Diagnostics, BioSimilars, CANCER BIOLOGY & Innovations in Cancer Therapy, Cancer Prevention: Research & Programs, Cell Biology, Signaling & Cell Circuits, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Drug Delivery Platform Technology, Pharmaceutical R&D Investment, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Technology Transfer: Biotech and Pharmaceutical, tagged Antibody, Cancer - General, CD47, CD47-SIRPα pathway, Chemotherapy, Integrins, macrophages, monoclonal antibody, Phagocytic cells, PI3K/AKT pathway, radiotherapy, Signal-regulatory protein alpha, Signal-regulatory protein-alpha (SIRPα), Stanford University, Stanford University School of Medicine, Thrombospondin 1, Thrombospondin-1 (TSP-1), Tilda Barliya, Trastuzumab on May 7, 2013| 7 Comments »

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 melanoma, prostate 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.

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 well. Clinical 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/S095279151200012X. http://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 http://pharmaceuticalintelligence.com/2013/03/03/treatment-for-metastatic-her2-breast-cancer/

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

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

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Treatment for Metastatic HER2 Breast Cancer

Posted in Advanced Drug Manufacturing Technology, Biomarkers & Medical Diagnostics, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Drug Delivery Platform Technology, FDA Regulatory Affairs, Genome Biology, Health Economics and Outcomes Research, Health Law & Patient Safety, International Global Work in Pharmaceutical, Molecular Genetics & Pharmaceutical, Personalized and Precision Medicine & Genomic Research, Pharmaceutical Industry Competitive Intelligence, Pharmaceutical R&D Investment, Population Health Management, Genetics & Pharmaceutical, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Technology Transfer: Biotech and Pharmaceutical, tagged antibody-drug conjugate, breast cancer, cytotoxicity, disease-free survival, DM1, Food and Drug Administration, Genentech, GlaxoSmithKline, HER2, ImmunoGen, Indianapolis, mertansine, metastatic, response rate, T-DM1, taxane, Trastuzumab, Trastuzumab emtansine on March 3, 2013| 10 Comments »

Treatment for Metastatic HER2 Breast Cancer

Word Cloud By Danielle Smolyar

Reporter: Larry H Bernstein, MD, FCAP
Leaders in Pharmaceutical Innovation
http://pharmaceuticalintelligence.com/2013/03/03/9680/Treatment for Metastatic HER2 Breast Cancer 

FDA Approves New Treatment for Metastatic HER2 Breast Cancer (antibody-drug conjugate)

T-DM1 is indicated for patients who were previously treated with the anti-HER2 therapy trastuzumab (Herceptin, Genentech) and a taxane chemotherapy.

Feb 22, 2013      http://www.medscape.com/viewarticle/779751

http://www.medscape.com/Oncology Medscape/FDA Approves New Treatment for Metastatic HER2 Breast Cancer (antibody-drug conjugate)

The US Food and Drug Administration (FDA) today approved ado-trastuzumab emtansine (Kadcyla, Genentech), also known as T-DM1, for the treatment of patients with HER2-positive metastatic breast cancer.
T-DM1 is indicated for patients who were previously treated with

• the anti-HER2 therapy trastuzumab (Herceptin, Genentech) and a taxane chemotherapy.

This product offers a new twist on an older product; it is an antibody–drug conjugate in which the

• HER2-targeted antibody trastuzumab
• is chemically linked to the cytotoxin mertansine (DM1).

The antibody homes in on HER2 breast cancer cells, delivering the chemotherapy directly to the tumor, which reduces the risk for toxicity.  According to Richard Pazdur, MD, at the FDA Center for Drug Evaluation and Research, T-DM1 carries the drug-conjugate

• directly to the cancer site
• to shrink the tumor,
• slow disease progression, and
• prolong survival .

It is the fourth drug approved that targets the HER2 protein. Apart from lapatinib, which is marketed by GlaxoSmithKline, all the other HER2-targeted products have been developed and are marketed by Genentech/Roche. For T-DM1, the proprietary technology involved in the DM1 portion of the product was developed by ImmunoGen, working in collaboration with Genentech/Roche.

In the pivotal phase 3 EMILIA study, patients receiving T-DM1 survived nearly 6 months longer than patients receiving the standard therapy of

• lapatinib (Tykerb) plus capecitabine (Xeloda) (median overall survival, 30.9 vs 25.1 months).

There were fewer grade 3 or higher (severe) adverse events with TDM-1 than with standard therapy

• 43.1% vs. 59.2%)

The approval represents a “momentous” day in breast cancer, said Kathy Miller, MD, from Indiana University in Indianapolis, in her Miller on Oncology Medscape blog.

• HER2-positive patients with metastatic disease have a therapy that offers prolonged disease control with less toxicity

 T-DM1 was more effective in EMILIA than standard therapy on every outcome:

• overall response rate,
• disease-free survival,
• progression-free survival, and
• overall survival.

Herceptin Fab (antibody) – light and heavy chains (Photo credit: Wikipedia)

Ribbon diagram of the Fab fragment of , a , bound to the extracellular domain of HER2. Created using Accelrys DS Visualizer Pro 1.6 and . ; Legend Trastuzumab Fab fragment, Trastuzumab Fab fragment, HER2, extracellular domain (Photo credit: Wikipedia)

Breast cancer (Infiltrating ductal carcinoma of the breast) assayed with anti HER-2 (ErbB2) antibody. (Photo credit: Wikipedia)

English: Breast cancer incidence by age in women in the United Kingdom 2006-2008. Reference: Excel chart for Figure 1.1: Breast Cancer (C50), Average Number of New Cases per Year and Age-Specific Incidence Rates, UK, 2006-2008 at Breast cancer – UK incidence statistics at Cancer Research UK. Section updated 18/07/11. (Photo credit: Wikipedia)

Related articles

• Bel Marra Health Reports on a New Study: Software Originally Used for Star Gazing Now Being Used to Analyze Breast Cancer Tissue (prweb.com)
• Breast Cancer Stem Cells Express HER2, Even In ‘Negative’ Tumors, Study Finds (medicalnewstoday.com)
• http://pharmaceuticalintelligence.com/2013/03/02/recurrence-risk-for-breast-cancer/
• http://pharmaceuticalintelligence.com/2013/01/29/in-focus-triple-negative-breast-cancer/

• http://pharmaceuticalintelligence.com/2013/01/17/mechanism-involved-in-breast-cancer-cell-growth-function-in-early-detection-treatment/

• http://pharmaceuticalintelligence.com/2013/01/10/the-molecular-pathology-of-breast-cancer-progression/
• http://pharmaceuticalintelligence.com/2012/12/24/breast-cancer-genomic-profiling-to-predict-survival-combination-of-histopathology-and-gene-expression-analysis/
• http://pharmaceuticalintelligence.com/2012/12/09/naotech-therapy-for-breast-cancer/
• http://pharmaceuticalintelligence.com/2012/09/18/breast-cancer-drug-resistance-and-biopharmaceutical-targets/
• http://venturebeat.com/2013/01/27/the-personalized-medicine-revolution-is-almost-here/

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