. 2014 Jul;4().
doi: 10.3389/fonc.2014.00141.

Co-development of diagnostic vectors to support targeted therapies and theranostics: essential tools in personalized cancer therapy

Nicholas C Nicolaides 1 Daniel J O'Shannessy 1 Earl Albone 1 Luigi Grasso 1 
  • PMID: 24982846
  •     51 References
  •     10 citations


Novel technologies are being developed to improve patient therapy through the identification of targets and surrogate molecular signatures that can help direct appropriate treatment regimens for efficacy and drug safety. This is particularly the case in oncology whereby patient tumor and biofluids are routinely isolated and analyzed for genetic, immunohistochemical, and/or soluble markers to determine if a predictive biomarker signature (i.e., mutated gene product, differentially expressed protein, altered cell surface antigen, etc.) exists as a means for selecting optimal treatment. These biomarkers may be drug-specific targets and/or differentially expressed nucleic acids, proteins, or cell lineage profiles that can directly affect the patient's disease tissue or immune response to a therapeutic regimen. Improvements in diagnostics that can prescreen predictive response biomarker profiles will continue to optimize the ability to enhance patient therapy via molecularly defined disease-specific treatment. Conversely, patients lacking predictive response biomarkers will no longer needlessly be exposed to drugs that are unlikely to provide clinical benefit, thereby enabling patients to pursue other therapeutic options and lowering overall healthcare costs by avoiding futile treatment. While patient molecular profiling offers a powerful tool to direct treatment options, the difficulty in identifying disease-specific targets or predictive biomarker signatures that stratify a significant fraction within a disease indication remains challenging. A goal for drug developers is to identify and implement new strategies that can rapidly enable the development of beneficial disease-specific therapies for broad patient-specific targeting without the need of tedious predictive biomarker discovery and validation efforts, currently a bottleneck for development timelines. Successful strategies may gain an advantage by employing repurposed, less-expensive existing agents while potentially improving the therapeutic activity of novel, target-specific therapies that may otherwise have off-target toxicities or less efficacy in cells exhibiting certain pathways. Here, we discuss the use of co-developing diagnostic-targeting vectors to identify patients whose malignant tissue can specifically uptake a targeted anti-cancer drug vector prior to treatment. Using this system, a patient can be predetermined in real-time as to whether or not their tumor(s) can specifically uptake a drug-linked diagnostic vector, thus inferring the uptake of a similar vector linked to an anti-cancer agent. If tumor-specific uptake is observed, then the patient may be suitable for drug-linked vector therapy and have a higher likelihood of clinical benefit while patients with no tumor uptake should consider other therapeutic options. This approach offers complementary opportunities to rapidly develop broad tumor-specific agents for use in personalized medicine.

Keywords: CDx; TM601; co-development; companion diagnostics; nanoparticles; naturally occurring proteins; personalized medicine; theranostics.

Brentuximab vedotin for the treatment of CD30+ lymphomas.
Kelley V Foyil, Nancy L Bartlett.
Immunotherapy, 2011 Apr 06; 3(4). PMID: 21463188
From cancer genomes to oncogenic drivers, tumour dependencies and therapeutic targets.
Cheryl Eifert, R Scott Powers.
Nat Rev Cancer, 2012 Jun 29; 12(8). PMID: 22739505
Lutetium-labelled peptides for therapy of neuroendocrine tumours.
B L R Kam, J J M Teunissen, +4 authors, D J Kwekkeboom.
Eur J Nucl Med Mol Imaging, 2012 Mar 06; 39 Suppl 1. PMID: 22388631    Free PMC article.
Diversity of Conus neuropeptides.
B M Olivera, J Rivier, +7 authors, L J Cruz.
Science, 1990 Jul 20; 249(4966). PMID: 2165278
Highly Cited.
Annexin A2 is a molecular target for TM601, a peptide with tumor-targeting and anti-angiogenic effects.
Kamala Kesavan, Judson Ratliff, +5 authors, Douglas B Jacoby.
J Biol Chem, 2009 Dec 19; 285(7). PMID: 20018898    Free PMC article.
Mining the biodiversity of plants: a revolution in the making.
Vincenzo De Luca, Vonny Salim, Sayaka Masada Atsumi, Fang Yu.
Science, 2012 Jun 30; 336(6089). PMID: 22745417
Cure of xenografted human carcinomas by BR96-doxorubicin immunoconjugates.
P A Trail, D Willner, +6 authors, K E Hellström.
Science, 1993 Jul 09; 261(5118). PMID: 8327892
Experimental α-particle radioimmunotherapy of breast cancer using 227Th-labeled p-benzyl-DOTA-trastuzumab.
Nasir Abbas, Helen Heyerdahl, +3 authors, Jostein Dahle.
EJNMMI Res, 2012 Jan 05; 1(1). PMID: 22214432    Free PMC article.
Understanding the economic value of molecular diagnostic tests: case studies and lessons learned.
Adrian Towse, Diego Ossa, +2 authors, Louis Garrison.
J Pers Med, 2013 Jan 01; 3(4). PMID: 25562729    Free PMC article.
Inhibitors of the anaplastic lymphoma kinase.
Luca Mologni.
Expert Opin Investig Drugs, 2012 May 23; 21(7). PMID: 22612599
Gene expression profiling predicts clinical outcome of breast cancer.
Laura J van 't Veer, Hongyue Dai, +13 authors, Stephen H Friend.
Nature, 2002 Feb 02; 415(6871). PMID: 11823860
Highly Cited.
Randomized controlled trial of yttrium-90-labeled ibritumomab tiuxetan radioimmunotherapy versus rituximab immunotherapy for patients with relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin's lymphoma.
Thomas E Witzig, Leo I Gordon, +10 authors, Christine A White.
J Clin Oncol, 2002 May 16; 20(10). PMID: 12011122
Highly Cited.
Comparison of prognostic genomic predictors in colorectal cancer.
Yun-Yong Park, Sung Sook Lee, +10 authors, Ju-Seog Lee.
PLoS One, 2013 Apr 30; 8(4). PMID: 23626670    Free PMC article.
Chlorotoxin, a scorpion-derived peptide, specifically binds to gliomas and tumors of neuroectodermal origin.
Susan A Lyons, Jeffrey O'Neal, Harald Sontheimer.
Glia, 2002 Jul 12; 39(2). PMID: 12112367
Meta-analysis of cancer gene expression signatures reveals new cancer genes, SAGE tags and tumor associated regions of co-regulation.
Ersen Kavak, Mustafa Unlü, Monica Nistér, Ahmet Koman.
Nucleic Acids Res, 2010 Jul 14; 38(20). PMID: 20621981    Free PMC article.
Claudin-4: a new target for pancreatic cancer treatment using Clostridium perfringens enterotoxin.
P Michl, M Buchholz, +7 authors, T M Gress.
Gastroenterology, 2001 Aug 28; 121(3). PMID: 11522752
Diabodies: small bispecific antibody fragments.
P Holliger, G Winter.
Cancer Immunol Immunother, 1998 Jan 22; 45(3-4). PMID: 9435855
Venomics as a drug discovery platform.
Pierre Escoubas, Glenn F King.
Expert Rev Proteomics, 2009 Jun 06; 6(3). PMID: 19489692
The causes and consequences of genetic heterogeneity in cancer evolution.
Rebecca A Burrell, Nicholas McGranahan, Jiri Bartek, Charles Swanton.
Nature, 2013 Sep 21; 501(7467). PMID: 24048066
Highly Cited. Review.
Pharmacokinetics and biodistribution of genetically engineered antibodies.
Surinder K Batra, Maneesh Jain, +2 authors, David Colcher.
Curr Opin Biotechnol, 2002 Dec 17; 13(6). PMID: 12482521
Techniques for using Bexxar for the treatment of non-Hodgkin's lymphoma.
David W Seldin.
J Nucl Med Technol, 2002 Aug 21; 30(3). PMID: 12186959
Characterization of the human folate receptor alpha via novel antibody-based probes.
Daniel J O'Shannessy, Elizabeth B Somers, +9 authors, Nicholas C Nicolaides.
Oncotarget, 2011 Dec 30; 2(12). PMID: 22204844    Free PMC article.
Dissecting therapeutic resistance to RAF inhibition in melanoma by tumor genomic profiling.
Nikhil Wagle, Caroline Emery, +9 authors, Levi A Garraway.
J Clin Oncol, 2011 Mar 09; 29(22). PMID: 21383288    Free PMC article.
Highly Cited.
PRECEDENT: a randomized phase II trial comparing vintafolide (EC145) and pegylated liposomal doxorubicin (PLD) in combination versus PLD alone in patients with platinum-resistant ovarian cancer.
R Wendel Naumann, Robert L Coleman, +17 authors, Richard A Messmann.
J Clin Oncol, 2013 Oct 16; 31(35). PMID: 24127448
Agents that bind annexin A2 suppress ocular neovascularization.
Raquel Lima e Silva, Jikui Shen, +5 authors, Peter A Campochiaro.
J Cell Physiol, 2010 Jul 08; 225(3). PMID: 20607799    Free PMC article.
Shifting emphasis from pharmacogenomics to theragnostics.
Vural Ozdemir, Bryn Williams-Jones, +3 authors, Christopher Reist.
Nat Biotechnol, 2006 Aug 11; 24(8). PMID: 16900136    Free PMC article.
Recent advances in the use of protein transduction domains for the delivery of peptides, proteins and nucleic acids in vivo.
Eric L Snyder, Steven F Dowdy.
Expert Opin Drug Deliv, 2005 Nov 22; 2(1). PMID: 16296734
Nanoparticle-aptamer bioconjugates: a new approach for targeting prostate cancer cells.
Omid C Farokhzad, Sangyong Jon, +3 authors, Robert Langer.
Cancer Res, 2004 Nov 03; 64(21). PMID: 15520166
Highly Cited.
Advances in targeted therapeutic agents.
Nicholas C Nicolaides, Philip M Sass, Luigi Grasso.
Expert Opin Drug Discov, 2010 Nov 01; 5(11). PMID: 22827748
Phase II study of the antibody drug conjugate trastuzumab-DM1 for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer after prior HER2-directed therapy.
Howard A Burris, Hope S Rugo, +12 authors, Joyce A O'Shaughnessy.
J Clin Oncol, 2010 Dec 22; 29(4). PMID: 21172893
Highly Cited.
Purification and characterization of chlorotoxin, a chloride channel ligand from the venom of the scorpion.
J A DeBin, J E Maggio, G R Strichartz.
Am J Physiol, 1993 Feb 01; 264(2 Pt 1). PMID: 8383429
Molecular imaging of a cancer-targeting theragnostics probe using a nucleolin aptamer- and microRNA-221 molecular beacon-conjugated nanoparticle.
Jin Kyeoung Kim, Kyung-Ju Choi, +2 authors, Soonhag Kim.
Biomaterials, 2011 Sep 29; 33(1). PMID: 21944470
Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer.
Soonmyung Paik, Gong Tang, +11 authors, Norman Wolmark.
J Clin Oncol, 2006 May 25; 24(23). PMID: 16720680
Highly Cited.
Targeted delivery of antitumoral therapy to glioma and other malignancies with synthetic chlorotoxin (TM-601).
Adam N Mamelak, Douglas B Jacoby.
Expert Opin Drug Deliv, 2007 Mar 06; 4(2). PMID: 17335414
Improved survival with vemurafenib in melanoma with BRAF V600E mutation.
Paul B Chapman, Axel Hauschild, +26 authors, BRIM-3 Study Group.
N Engl J Med, 2011 Jun 07; 364(26). PMID: 21639808    Free PMC article.
Highly Cited.
Sphingomyelin is important for the cellular entry and intracellular localization of Helicobacter pylori VacA.
Vijay R Gupta, Brenda A Wilson, Steven R Blanke.
Cell Microbiol, 2010 Jun 16; 12(10). PMID: 20545942    Free PMC article.
Chlorotoxin labeled magnetic nanovectors for targeted gene delivery to glioma.
Forrest M Kievit, Omid Veiseh, +4 authors, Miqin Zhang.
ACS Nano, 2010 Aug 25; 4(8). PMID: 20731441    Free PMC article.
Intratumoral heterogeneity of HER2/neu expression and its consequences for the management of advanced breast cancer.
P H Cottu, J Asselah, +5 authors, A Vincent-Salomon.
Ann Oncol, 2008 Feb 15; 19(3). PMID: 18272907
Penetratin improves tumor retention of single-chain antibodies: a novel step toward optimization of radioimmunotherapy of solid tumors.
Maneesh Jain, Subhash C Chauhan, +3 authors, Surinder K Batra.
Cancer Res, 2005 Sep 06; 65(17). PMID: 16140953
Pivotal study of iodine I 131 tositumomab for chemotherapy-refractory low-grade or transformed low-grade B-cell non-Hodgkin's lymphomas.
M S Kaminski, A D Zelenetz, +10 authors, J M Vose.
J Clin Oncol, 2001 Oct 02; 19(19). PMID: 11579112
Highly Cited.
Claudin-1 is a hepatitis C virus co-receptor required for a late step in entry.
Matthew J Evans, Thomas von Hahn, +7 authors, Charles M Rice.
Nature, 2007 Feb 28; 446(7137). PMID: 17325668
Highly Cited.
Preclinical evaluation of MORAb-003, a humanized monoclonal antibody antagonizing folate receptor-alpha.
Wolfgang Ebel, Eric L Routhier, +11 authors, Luigi Grasso.
Cancer Immun, 2007 Mar 10; 7. PMID: 17346028    Free PMC article.
In vivo imaging of siRNA delivery and silencing in tumors.
Zdravka Medarova, Wellington Pham, +2 authors, Anna Moore.
Nat Med, 2007 Feb 27; 13(3). PMID: 17322898
Highly Cited.
Discovery and development of the G-rich oligonucleotide AS1411 as a novel treatment for cancer.
Paula J Bates, Damian A Laber, +2 authors, John O Trent.
Exp Mol Pathol, 2009 May 21; 86(3). PMID: 19454272    Free PMC article.
Highly Cited. Review.
Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia.
Brian J Druker, François Guilhot, +30 authors, IRIS Investigators.
N Engl J Med, 2006 Dec 08; 355(23). PMID: 17151364
Highly Cited.
Tumor paint: a chlorotoxin:Cy5.5 bioconjugate for intraoperative visualization of cancer foci.
Mandana Veiseh, Patrik Gabikian, +14 authors, James M Olson.
Cancer Res, 2007 Jul 20; 67(14). PMID: 17638899
Highly Cited.
Strategies in the design of nanoparticles for therapeutic applications.
Robby A Petros, Joseph M DeSimone.
Nat Rev Drug Discov, 2010 Jul 10; 9(8). PMID: 20616808
Highly Cited. Review.
Site-specific conjugation of a cytotoxic drug to an antibody improves the therapeutic index.
Jagath R Junutula, Helga Raab, +28 authors, William Mallet.
Nat Biotechnol, 2008 Jul 22; 26(8). PMID: 18641636
Highly Cited.
Crotamine mediates gene delivery into cells through the binding to heparan sulfate proteoglycans.
Fábio Dupart Nascimento, Mirian A F Hayashi, +7 authors, Irina Kerkis.
J Biol Chem, 2007 May 11; 282(29). PMID: 17491023
High affinity restricts the localization and tumor penetration of single-chain fv antibody molecules.
G P Adams, R Schier, +5 authors, L M Weiner.
Cancer Res, 2001 Jun 19; 61(12). PMID: 11406547
Highly Cited.
Assessing the clinical utility of diagnostics used in drug therapy.
J Woodcock.
Clin Pharmacol Ther, 2010 Oct 29; 88(6). PMID: 20981005
Drug-diagnostics co-development in oncology.
Jan Trøst Jørgensen.
Front Oncol, 2014 Aug 20; 4. PMID: 25136515    Free PMC article.
Multidisciplinary efforts driving translational theranostics.
Tony Y Hu.
Theranostics, 2014 Oct 07; 4(12). PMID: 25285169    Free PMC article.
A biological perspective toward the interaction of theranostic nanoparticles with the bloodstream - what needs to be considered?
Martin J D Clift, Jean-François Dechézelles, Barbara Rothen-Rutishauser, Alke Petri-Fink.
Front Chem, 2015 Feb 26; 3. PMID: 25713796    Free PMC article.
Personalized health care beyond oncology: new indications for immunoassay-based companion diagnostics.
Richard Batrla, Bruce W M Jordan.
Ann N Y Acad Sci, 2015 Apr 14; 1346(1). PMID: 25866164    Free PMC article.
Companion diagnostics and molecular imaging-enhanced approaches for oncology clinical trials.
Ronald L Van Heertum, Robert Scarimbolo, +2 authors, Michael O'Neal.
Drug Des Devel Ther, 2015 Sep 24; 9. PMID: 26392755    Free PMC article.
Diapeutic cancer-targeting alkylphosphocholine analogs may advance management of brain malignancies.
Ray R Zhang, Kyle I Swanson, +2 authors, John S Kuo.
CNS Oncol, 2016 Sep 13; 5(4). PMID: 27616199    Free PMC article.
The New Age of -omics in Urothelial Cancer - Re-wording Its Diagnosis and Treatment.
Theodora Katsila, Michalis Liontos, +2 authors, Dimitrios Kardamakis.
EBioMedicine, 2018 Feb 13; 28. PMID: 29428524    Free PMC article.
Theranostic pH-sensitive nanoparticles for highly efficient targeted delivery of doxorubicin for breast tumor treatment.
Changqie Pan, Yuqing Liu, +4 authors, Wangjun Liao.
Int J Nanomedicine, 2018 Mar 10; 13. PMID: 29520140    Free PMC article.
RNA-based drugs and vaccines.
Kenneth Lundstrom.
Expert Rev Vaccines, 2014 Sep 16; 14(2). PMID: 25220891    Free PMC article.
Biomarker-Drug and Liquid Biopsy Co-development for Disease Staging and Targeted Therapy: Cornerstones for Alzheimer's Precision Medicine and Pharmacology.
Harald Hampel, Edward J Goetzl, +2 authors, Andrea Vergallo.
Front Pharmacol, 2019 Apr 16; 10. PMID: 30984002    Free PMC article.