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PubMed2007

Chemical modification of therapeutic drugs or drug vector systems to achieve targeted therapy: looking for the grail.

Most therapeutic drugs distribute to the whole body, which results in general toxicity and poor acceptance of the treatments by patients. The targeted delivery of chemotherapeutics to defined cells, either stromal or cancer cells in cancer lesions, or defined inflammatory cells in immunological disorders, is one of the main challenges and a very active field of research in the development of treatment strategies to minimize side-effects of drugs. Disease-associated cells express molecules, including proteases, receptors, or adhesion molecules, that are different or differently expressed than their normal counterparts. Therefore one goal in the field of targeted therapies is to develop chemically derivatized drugs or drug vectors able to target defined cells via specific recognition mechanisms and also able to overcome biological barriers. This article will review the approaches which have been explored to achieve these goals and will discuss in more detail three examples (i) the use of nanostructures to take advantage of increased vascular permeability in some human diseases, (ii) the targeting of therapeutic drugs to an organ, the brain, protected against foreign molecules by the blood-brain barrier, and (iii) the use of the folate receptor to target either tumor cells or activated macrophages.

Blood-Brain Barrier↗
PubMed1999

Farnesyl protein transferase inhibitors and other therapies targeting the Ras signal transduction pathway.

The year 2000 will be a significant date for the field of Ras-related therapies since numerous agents will have Phase II clinical efficacy data maturing to provide proof of principle for this cancer treatment strategy. These data will also provide an important milestone for the cancer research community since these molecules represent a small vanguard of oncology drug discovery projects predicated on molecular targets. We can only hope that these agents are a successful harbinger for the formidable number of targeted therapies that will be entering development pipelines in the coming years.

Alkyl and Aryl Transferases↗
PubMed2005

Novel targeted therapies to overcome imatinib mesylate resistance in chronic myeloid leukemia (CML).

Imatinib mesylate (Gleevec) was developed as the first molecularly targeted therapy that specifically inhibits the BCR-ABL tyrosine kinase activity in patients with Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML). Due to its excellent hematologic and cytogenetic responses, particularly in patients with chronic phase CML, imatinib has moved towards first-line treatment for newly diagnosed CML. Nevertheless, resistance to the drug has been frequently reported and is attributed to the fact that transformation of hematopoietic stem cells by BCR-ABL is associated with genomic instability. Point mutations within the ABL tyrosine kinase of the BCR-ABL oncoprotein are the major cause of resistance, though overexpression of the BCR-ABL protein and novel acquired cytogenetic aberrations have also been reported. A variety of strategies derived from structural studies of the ABL-imatinib complex have been developed, resulting in the design of novel ABL inhibitors, including AMN107, BMS-354825, ON012380 and others. The major goal of these efforts is to create new drugs that are more potent than imatinib and/or more effective against imatinib-resistant BCR-ABL clones. Some of these drugs have already been successfully tested in preclinical studies where they show promising results. Additional approaches are geared towards targeting the expression or stability of the BCR-ABL kinase itself or targeting signaling pathways that are chronically activated and required for transformation. In this review, we will discuss the underlying mechanisms of resistance to imatinib and novel targeted approaches to overcome imatinib resistance in CML.

Antineoplastic Agents↗
PubMed2004

[Tumor suppressor gene p53 and molecular targeting therapy].

p53 is a molecule which is activated upon a DNA stress, such as gamma irradiation, UV, hypoxia, virus infection, and DNA damage, leading protection of cells by inducing target genes. The molecules activated by p53 induce apoptosis, cell cycle arrest, and DNA repair to conserve genome. In order to kill cancer cells, many strategies targeting p53 have been reported. Preclinical studies have demonstrated that overexpression of wt-p53 by adenovirus vector is capable of inducing apoptosis in cancers. Furthermore, restoration of mt-p53 into wild type by compound has been under development. In this review, clinical application of molecular targeting therapy for p53 is discussed.

Apoptosis↗
PubMed2006

Lack of methylthioadenosine phosphorylase expression in mantle cell lymphoma is associated with shorter survival: implications for a potential targeted therapy.

PURPOSE: To determine the methylthioadenosine phosphorylase (MTAP) gene alterations in mantle cell lymphoma (MCL) and to investigate whether the targeted inactivation of the alternative de novo AMP synthesis pathway may be a useful therapeutic strategy in tumors with inactivation of this enzyme. EXPERIMENTAL DESIGN: MTAP gene deletion and protein expression were studied in 64 and 52 primary MCL, respectively, and the results were correlated with clinical behavior. Five MCL cell lines were analyzed for MTAP expression and for the in vitro sensitivity to L-alanosine, an inhibitor of adenylosuccinate synthetase, and hence de novo AMP synthesis. RESULTS: No protein expression was detected in 8 of 52 (15%) tumors and one cell line (Granta 519). Six of these MTAP negative tumors and Granta 519 cell line had a codeletion of MTAP and p16 genes; one case showed a deletion of MTAP, but not p16, and one tumor had no deletions in neither of these genes. Patients with MTAP deletions had a significant shorter overall survival (mean, 16.1 months) than patients with wild-type MTAP (mean, 63.6 months; P < 0.0001). L-Alanosine induced cytotoxicity and activation of the intrinsic mitochondrial-dependent apoptotic pathway in MCL cells. 9-beta-D-Erythrofuranosyladenine, an analogue of 5'-methylthioadenosine, selectively rescued MTAP-positive cells from L-alanosine toxicity. CONCLUSIONS: MTAP gene deletion and lack of protein expression are associated with poor prognosis in MCL and might identify patients who might benefit from treatment with de novo AMP synthesis pathway-targeted therapies.

Base Sequence↗
PubMed2004

Screening a combinatorial peptide library to develop a human glandular kallikrein 2-activated prodrug as targeted therapy for prostate cancer.

OBJECTIVE: Prostate cancer cells secrete the unique protease human glandular kallikrein 2 (hK2) that represents a target for proteolytic activation of cytotoxic prodrugs. The objective of this study was to identify hK2-selective peptide substrates that could be coupled to a cytotoxic analogue of thapsigargin, a potent inhibitor of the sarcoplasmic/endoplasmic reticulum calcium ATPase pump that induces cell proliferation-independent apoptosis through dysregulation of intracellular calcium levels. METHODS: To identify peptide sequence requirements for hK2, a combination of membrane-bound peptides (SPOT analysis) and combinatorial chemistry using fluorescence-quenched peptide substrates was used. Peptide substrates were then coupled to 8-O-(12[L-leucinoylamino]dodecanoyl)-8-O-debutanoylthapsigargin (L12ADT), a potent analogue of thapsigargin, to produce a prodrug that was then characterized for hK2 hydrolysis, plasma stability, and in vitro cytotoxicity. RESULTS: Both techniques indicated that a peptide with two arginines NH2-terminal of the scissile bond produced the highest rates of hydrolysis. A lead peptide substrate with the sequence Gly-Lys-Ala-Phe-Arg-Arg (GKAFRR) was hydrolyzed by hK2 with a Km of 26.5 micromol/L, kcat of 1.09 s(-1), and a kcat/Km ratio of 41,132 s(-1) mol/L(-1). The GKAFRR-L12ADT prodrug was rapidly hydrolyzed by hK2 and was stable in plasma, whereas the GKAFRR-L peptide substrate was unstable in human plasma. The hK2-activated thapsigargin prodrug was not activated by cathepsin B, cathepsin D, and urokinase but was an excellent substrate for plasmin. The GKAFRR-L12ADT was selectively cytotoxic in vitro to cancer cells in the presence of enzymatically active hK2. CONCLUSION: The hK2-activated thapsigargin prodrug represents potential novel targeted therapy for prostate cancer.

Amino Acid Sequence↗
PubMed2004

Targeted therapies for non-small-cell lung cancer: biology, rationale, and preclinical results from a radiation oncology perspective.

The epidermal growth factor receptor (EGFR) is overexpressed in the majority of non-small-cell lung cancers (NSCLCs). This presents an opportune target for new treatment strategies designed to selectively interfere with the cancer cell growth cycle. Recent investigations into the biology of the EGFR and its downstream signaling pathways have reminded us of the complexity of cancer cell communications from the cytoplasm to the nucleus. Multiple pathways are activated with stimulation of the autocrine and paracrine EGFR loop, from the ras-raf-MEK activation of ERK 1/2 to the P13K-Akt pathway, each playing an important role in cancer cell survival, invasion, and angiogenesis. Preclinical studies have demonstrated that molecules targeting the EGFR, either through extracellular blockade or intracellular interference with the EGFR-associated tyrosine kinase, reversibly or irreversibly, inhibit cancer cell growth. Potent antitumor effects have been observed in human tumor xenograft models. Preclinical studies have also demonstrated cooperative effects when anti-EGFR agents are combined with radiation or chemotherapy. Many of these agents have now entered into advanced human clinical trials with modest dose-related toxicity despite chronic administration. Encouraging response rates with single-agent targeted therapy have been reported in heavily pretreated patients with advanced NSCLC. In addition, agents targeting the angiogenic pathway, which plays a key role in the regulation of angiogenesis, may play an important role in enhancing the efficacy of anti-EGFR agents. This article will focus on the biology, rationale, and preclinical studies with targeted anti-EGFR and antiangiogenic therapies for the management of NSCLC.

Angiogenesis Inhibitors↗
PubMed2006

T-cell-targeted therapies in rheumatoid arthritis.

T cells regulate the disease process in rheumatoid arthritis (RA) on multiple levels and represent a logical choice for anti-inflammatory therapy. In the inflamed joint they promote neoangiogenesis and lymphoid organogenesis, and stimulate synoviocyte proliferation and development of bone-eroding osteoclasts. The design of T-cell-targeted therapies for RA needs to take into account the uniqueness of T-cell generation, turnover and differentiation in affected patients. Patients accumulate 'old' T cells that respond to alternate regulatory signals because of an accelerated immune aging process; any therapeutic interventions that increase the replicative stress of T cells should, therefore, be avoided. Instead, therapeutic approaches that raise the threshold for T-cell activation are more promising. As a rule, antigen-derived signals synergize with co-stimulatory signals to stimulate T cells; such co-stimulatory signals are now targeted in novel immunosuppressive therapies. An example is abatacept (soluble cytotoxic-T-lymphocyte-associated protein 4-immunoglobulin), which binds with high affinity to CD80/CD86 and effectively suppresses inflammatory activity in RA. The therapeutic benefits gained by disrupting T-cell co-stimulation indicate that the pathogenesis of RA is driven by a more generalized abnormality in T-cell activation thresholds rather than a highly selective action of arthritogenic antigens.

Arthritis, Rheumatoid↗
PubMed2005

[Synergistic role between rhIL-2 and adriamycin long circulating temperature-sensitive liposome in targeting therapy on tumor].

AIM: To observe the synergistic role between rhIL-2 and adriamycin long circulating temperature-sensitive liposome (ALTSL) in targeting therapy of H22 tumor-bearing mice and explore their anti-tumor mechanism. METHODS: The antitumor activity was evaluated by using the tumor's weight as an index. The prolongation rate of mouse life was calculated according to the survival time of the tumor-bearing mice. The killer activity of NK cells and the lymphocyte transformation rate were detected by the LDH and MTT colorimetry, respectively. The apoptosis of tumor cells and the expression of p53, Fas, Fas-L and Caspase-3 were analyzed by flow cytometry (FCM). The expression of IL-2 mRNA and IL-12 mRNA in splenocytes was determined by RT-PCR. The pathologic changes of tumor, heart, liver and kidney tissues of the tumor-bearing mice were observed under light microscope. RESULTS: The tumoristatic rate of rhIL-2+ALTSL (73.5%) was higher than that of adriamycin liposome (ADML) group (67.0%). The survival time of tumor-bearing mice in ALTSL and rhIL-2+ALTSL groups was significantly extended as compared with the NS group (treated with normal saline) and the free ADM group (P <0.01 or P <0.05). The killer activities of NK cells of ALTSL group and rhIL-2+ALTSL group were higher than those of the NS and free ADM groups, and was highest in rhIL-2+ALTSL group. The lymphocyte transformation rate of ALTSL+rhIL-2 group markedly increased ( P <0.01) as compared with the free ADM group. The result of RT-PCR indicated that the expression of IL-2 mRNA and IL-12 mRNA in splenocytes in the adriamycin long circulating liposome (ALCL) group was significantly higher than that in the free ADM group. The enhancement of rhIL-2+ALTSL on expression of IL-2 mRNA and IL-12 mRNA was much stronger than that of ALTSL alone. The pathological examination indicated that in rhIL-2+ALTSL group, the tumor cells were mostly destroyed, and a large amount of lymphocytes and monocytes were found in tumor tissue. CONCLUSION: ALTSL can increase the anti-tumor effect and decreased the side-effects (such as the cytotoxicity) of ADM. rhIL-2+ALTSL can induce the apoptosis of tumor cells and enhance killer activities of T cells and NK cells. rhIL-2 and ALTSL can synergistically play the antitumor effect.

Animals↗
PubMed2003

Genetic and signaling pathway alterations in glioblastoma: relevance to novel targeted therapies.

Glioblastomas multiforme (GBM) is the most common malignant primary brain tumor in adults. GBM patients have a dismal prognosis, with a median survival of less than 1 year. During the past decade, significant advances have been made in our understanding of the molecular pathogenesis of these tumors. Specific genetic defects have been identified that appear to be important for the development, as well as maintenance of the malignant characteristics that are associated with GBM. Some of these genetic aberrations appear to have prognostic significance. However, even more exciting in this era of molecularly targeted therapy are the clues these gene alterations provide for identifying signaling mechanisms responsible for carcinogenesis, and for identifying potential therapeutic targets. Cancer drug therapy is currently undergoing a major transition with an attempt to move from the use of cytotoxic drugs towards the use of tumor mechanism-based drugs. Advances such as the decoding of the human genome, combinatorial chemistry, and gene expression profiling have led to an increase in the rate at which new drugs are being developed. In this review, we will describe the most common genetic and signaling pathway alterations that have relevance to new drug development for the treatment of GBM.

Animals↗
PubMed2005

[Expression of Her2/neu in locally advanced bladder cancer: implication for a molecular targeted therapy].

PURPOSE: The Her2/neu oncoprotein, belonging to the erbB-receptor family, is known to contribute to physiological mechanisms of cell proliferation by intrinsic tyrosine-kinase-activity. Overexpression has been shown for several tumors and is known to influence malignant cell proliferation, metastasis and angiogenesis. The clinical use of Her2-targeting agents has emerged in clinical research. In our study, we analyzed Her2/neu expression in urothelial tumors. MATERIALS AND METHODS: Her2/neu expression was evaluated immunohistochemically (IHC) in 127 patients undergoing radical cystectomy (DAKO- Herceptest). Additionally, fluorescent-in-situ-hybridisation (FISH) was carried out in all immunohistochemically "2+" cases (n = 41) to assess gene amplification. After grading the Her2/neu-overall status, Her2/neu expression was correlated with clinicopathological parameters and survival data. RESULTS: An immunohistochemical Her2/neu expression was found in 95 of 127 cases (74.8 %). Of all 41 cases with "2+" staining (32.2 %), 11 cases (26.8 %) showed positive amplification by FISH. Therefore, including the IHC 3+ cases, a Her2/neu overall status of 22 positive (17.3 %) tumors was assessed. Correlation with clinical data showed a relation to lymph node metastasis (P = 0.06), lymph vessel invasion (P = 0.07) and metastasis (P = 0.002). No further associations with other parameters nor with overall survival (P = 0.73) or disease-free survival (P = 0.63) were found. CONCLUSIONS: Her2/neu upregulation is found in invasive bladder cancer with significant differences in protein expression and gene amplification. The association with lymphogenic and distant metastases implicates a late event in carcinogenesis. Moreover, there was no further association with clinicopathological parameters and survival. The possible role of a molecular targeted therapy of advanced bladder cancer with Her2/neu targeting agents should be assessed in further clinical trials.

Adult↗
PubMed2002

p53 as a therapeutic target: unresolved issues on the road to cancer therapy targeting mutant p53.

As a tumor suppressor, p53 has a central role in oncogenesis: it inhibits the growth of abnormal cells and thus prevents cancer development. The frequent occurrence of p53 mutations in human cancer and its role as "guardian of the genome" has led to numerous investigations evaluating its role as a potential therapeutic target in terms of restoring wild type (wt) p53 and thereby either reverting the malignant phenotype or enhancing drug sensitivity. A critical evaluation of the available data suggests that following the restoration of wt p53 growth inhibition is an attainable goal, although induction of apoptosis would be more desirable. As for attempts to enhance drug sensitivity, the evidence suggest that this too can be accomplished, but how best to accomplish it remains to be explored. To properly evaluate these strategies, one must consider the known and putative roles of p53. Research conducted in the last decade has firmly established the importance of p53 in mediating the cell cycle arrest that occurs following DNA damage. However, during this same time, the role of p53 in mediating apoptosis has become increasingly less clear, even as the number of putative pro-apoptotic proteins transactivated by p53 has increased. Similarly unclear is how p53 makes a choice between cell cycle arrest or apoptosis, raising the possibility that p53 alone is not responsible for this crucial decision. Despite the existence of several crucial unresolved issues, strategies attempting to enhance the expression of the wt p53 phenotype in cancer cells deserve further investigation. Although the importance of p53 in maintaining an established malignant phenotype as well as its role in apoptosis and chemotherapy-induced cytotoxicity are far from settled, a subset of cancers may respond to these strategies.

Animals↗
PubMed2006

The impact of human EGFR kinase domain mutations on lung tumorigenesis and in vivo sensitivity to EGFR-targeted therapies.

To understand the role of human epidermal growth factor receptor (hEGFR) kinase domain mutations in lung tumorigenesis and response to EGFR-targeted therapies, we generated bitransgenic mice with inducible expression in type II pneumocytes of two common hEGFR mutants seen in human lung cancer. Both bitransgenic lines developed lung adenocarcinoma after sustained hEGFR mutant expression, confirming their oncogenic potential. Maintenance of these lung tumors was dependent on continued expression of the EGFR mutants. Treatment with small molecule inhibitors (erlotinib or HKI-272) as well as prolonged treatment with a humanized anti-hEGFR antibody (cetuximab) led to dramatic tumor regression. These data suggest that persistent EGFR signaling is required for tumor maintenance in human lung adenocarcinomas expressing EGFR mutants.

Adenocarcinoma↗
PubMed2004

Intracellular signaling triggered by antiphospholipid antibodies in platelets and endothelial cells: a pathway to targeted therapies.

Understanding the intracellular events triggered by antiphospholipid (aPL) antibodies in platelets and endothelial cells (ECs) is important in designing new modalities of targeted therapies for the treatment of thrombosis in Antiphospholipid Syndrome (APS). A recent study showed a significant increase in the expression of GPIIb/IIIa on platelets treated with aPL antibodies and a thrombin receptor peptide agonist (TRAP), and these effects were abrogated by hydroxychloroquine (HQ). Hydroxychloroquine has also been shown to reduce in vivo aPL-induced thrombus formation. Furthermore, aPL-enhanced thrombosis in vivo can be abrogated by infusions of a GPIIb/IIIa antagonist (1B5) monoclonal antibody, and aPL-mediated thrombophilia is not observed in GPIIb/IIIa-deficient mice. Treatment of platelets with aPL antibodies has resulted in a significant increase in p38 mitogen-activated protein kinase (p38MAPK) phosphorylation and aPL-induced platelet aggregation and thromboxane B2 (TXB2) production was abrogated by SB203580 (a p38MAPK inhibitor). aPL antibodies induce increased expression, function and transcription of tissue factor (TF) on EC. Activation of ECs and thrombogenicity of aPL in vivo can be reversed by treatment of the animals with statins. Upregulation of TF on ECs can also be abrogated by treatment of the cells with fluvastatin. There is also indication of activation of nuclear factor kappa B (NFkappaB), increase in phosphorylation of p38MAPK in ECs by aPL antibodies that can be reversed by specific inhibitors MG132 and SB203580, respectively. The data open the possibility to new treatment modalities that may include the use of hydroxychloroquine, statins, specific antagonists of GPIIb/IIIa (such as abciximab or equivalent) and specific p38MAPK inhibitors, after the completion of well-designed clinical studies.

Animals↗
PubMed2006

[EGFR-targeted therapies: what's new?].

Anti-EGFR molecules with monoclonal antibodies or tyrosine protein kinase inhibitors represent a strategy which remains promising as targeted therapies of cancers, despite some ambiguous results. This review proposes to expose the state of the art concerning the development of anti-EGFR molecules: rationale of this approach, analysis of the results obtained on the one hand by monoclonal antibodies and on the other hand by tyrosine kinase inhibitors. Finally, a presentation is done about possible predictive factors for a relevant use of these molecules in the future.

Antibodies, Monoclonal↗
PubMed2004

Targeted therapy for malignant gliomas.

The identification of markers that are associated with tumour but not normal tissue has allowed the development of highly-specific targeted therapies. Monoclonal antibodies, either alone or linked to radioisotopes or toxins, have provided a powerful tool for research, as well as the basis for promising therapeutic agents with less side effects than standard radiotherapy or chemotherapy. A new class of drugs, the tyrosine kinase inhibitors, which interfere with the function of key molecules in cancer-promoting pathways, have had a dramatic effect in haematological malignancy and are being trialled in solid tumours, including glioma. Although the problem of achieving specific, high-level delivery of these various agents to tumours in the brain remains a major issue, encouraging early results with some targeted agents support the attractive theoretical principles of this new paradigm. Further work to identify new molecular targets and to develop agents exploiting them, is needed, as well as confirmation of their safety and efficacy by clinical trials.

Antibodies, Monoclonal↗
PubMed1998

Tumor vasculature targeted therapies: getting the players organized.

Based on their location and central role in solid tumor growth, tumor vascular endothelial cells may present an attractive target for the delivery of therapeutic drugs or cells. The potency of blocking the tumor blood supply in eradicating solid tumors was demonstrated recently in a mouse model of tumor vasculature targeting (Huang et al., Science 275: 547-550, 1997). For clinical application of such strategies, tumor endothelium specific target epitopes need to be identified. Recent studies on angiogenesis have identified angiogenesis-related molecules as potential target epitopes. Among these are vascular endothelial growth factor (VEGF)/VEGF-receptor complex, alpha(v) integrins, and Tie receptor tyrosine kinases. Besides blockade of their signalling cascades leading to inhibition of angiogenesis, these epitopes may also be instrumental in tumor vessel specific delivery of therapeutics. Data on the efficacy of therapeutic modalities aimed at these, mostly heterogeneously distributed tumor endothelial epitopes are scarce, and sophisticated experimentation is required to rationalize the development of new therapeutic strategies. Importantly, only detailed evaluations in cancer patients will provide the blueprint for the development of clinically effective tumor vascular targeted therapies.

Animals↗
PubMed2004

Acute promyelocytic leukemia as a paradigm for targeted therapy.

Substantial progress has occurred in the treatment of acute promyelocytic leukemia (APL) because of improved understanding of the pathophysiology of the disease and identification of a molecular target. Novel agents such as all-trans retinoic acid (ATRA) (alone or combined with chemotherapy) and, more recently, arsenic trioxide have produced complete remission in most patients with newly diagnosed APL and/or relapsed or refractory disease, respectively. Use of these targeted therapies has resulted in evolution of the disease from one that was historically one of the most fatal subtypes of acute myeloid leukemia (AML) to one that appears curable in 70% to 80% of patients. The targeted approach to treatment of this disease can serve as a paradigm for the treatment of other leukemias.

Arsenic Trioxide↗