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Targeting GFR-mediated Signals with Cancer As VEGFR plays a key role in new blood vessel
Therapeutics formation, different antibodies against VEGFR are
designed to prevent angiogenesis and growth in
Accumulated understanding over the last 30 years cancer. [29-32] The combination of mAbs with different
of signaling pathways mediated by different GFRs antineoplastic drugs often increases effectiveness. Diverse
and their relationship with cancer progression has combinations of mAbs conjugated with different types of
led to the development of targeted agents for cancer drugs are currently in clinical trials.
treatment. There are at least 6 approaches to target
these pathways: (1) monoclonal antibodies (mAbs) Development of resistance against GFR-targeted mAbs is
against GFRs; (2) protein kinase inhibitors; (3) nucleic the foremost limitation to their clinical use. Resistance to
acid-based therapeutics for gene silencing (use of these antibodies can be either primary or acquired which
[33]
antisense RNA or short interfering RNA [siRNA] to develops within few months to years of treatment.
block receptor expression); (4) soluble receptors for Patients treated with trastuzumab monotherapy showed
growth factor ligands (“Traps”); (5) inhibitors of heat intrinsic (66-88%) and acquired resistance within one
[34]
shock proteins and (6) antagonists of signaling pathway year (15%) which resulted in loss of effectiveness.
proteins. Although in most cases the underlying mechanisms of
resistance remain poorly understood, in few cases resistance
Among these, the fi rst three strategies including have been linked to the compensatory pathways
mAbs, protein kinase inhibitors and nucleic acid-based mediated by other GFRs or mutations in downstream
therapeutics are designed to target the GFRs, and thus signaling pathways. For example, enhancement of
are highlighted in this review. Radiological responses IGF1R-mediated signal in anti-erbB2/HER2 (trastuzumab)
to targeted molecular agents used as monotherapy are antibody-treated breast cancer patients confers resistance
typically more limited compared to the conventional to treatment. Overexpression of membrane-associated
[35]
chemotherapy and radiotherapy. However, effects glycoprotein MUC4, PTEN-PI3K signaling pathways,
on progression-free survival have been observed. and elevated HER2 extracellular domain in serum are
Nowadays, targeted molecular agents are often combined also involved in trastuzumab resistance. Mutations
[34]
with chemo- or radiotherapy, mainly for two reasons: in K-Ras are responsible for primary resistance against
combination with chemo- or radio-therapy improves anti-EGFR antibodies in colorectal cancer. Treatment
[36]
effi cacy and the molecular specifi city of mAbs aids to regimen containing multiple mAbs against different
target tumor selectively. GFRs may conceivably increase resistance but may be
Monoclonal antibodies against GFRs unacceptably toxic. For example, cross-talk between
EGF- and IGF-mediated signaling pathways plays major
The development of hybridoma technology to produce roles in acquired resistance. Preclinical data suggest that
mAbs is the fi rst step in the process of turning the simultaneous blockade of the two pathways could be
dream of “magic bullets” for targeted treatment of advantageous in treatment. [37-40] However, a phase II trial
cancer a reality. A wide number of mAbs-based in colorectal cancer patients treated with cetuximab and
therapies have been approved by the Food and Drug cixitumumab failed to show any additional antitumor
Administration (FDA) for the treatment of different activity, and so this treatment regimen was eliminated
malignancies and many more are in clinical trials. from consideration in colorectal cancer patients refractory
[27]
These therapeutics act by directly blocking the function to EGFR inhibitors. [41,42] Mechanism-based combinations
of GFRs and/or by antibody-dependent cytotoxicity, of GFR mAbs will require case-by-case validation in
mediated by Fc fragment recognizing immune cells. preclinical and pilot clinical studies.
Antibody-drug conjugates are designed for targeted
drug delivery to cells expressing their cognate GFR. Protein kinase inhibitors
A variety of mAbs are used to modulate GFR functions Structural and functional analyses have paved the way to
in different indications [Table 3]. For example, the discovery and development of numerous protein kinase
humanized mAb, trastuzumab designed to target ErbB2 inhibitors, especially tyrosine kinase inhibitors (TKIs)
and approved by FDA in 1998, is successfully used to that inhibit the cytoplasmic kinase activity of growth
[28]
treat HER2+ metastatic breast cancer patients. The receptors and subsequently their downstream signaling
approval of the drug was further expanded in 2006 for cascades into the cells. Most of these compounds
women with cancer in breast and lymph node region as are hydrophobic in nature and, therefore, are orally
early stage therapy after primary therapy (lumpectomy, bioavailable. The majority of these agents rapidly
mastectomy). In October 2010, it was approved to use cross cell plasma membranes and compete with
for HER2-overexpressing, gastroesophageal junction phosphate donor adenosine tyrosine phosphate (ATP),
[43]
adenocarcinoma in combination with either cisplatin or phosphorylation substrates, or both. Many such
fl uoropyrimidines in patients who have not received any compounds have shown cytostatic effects in cancer cells
prior treatment. and animal models. Because of the “ druggability” of
[44]

194 Journal of Cancer Metastasis and Treatment ¦ Volume 1 ¦ Issue 3 ¦ October 15, 2015 ¦