Good Antitumor Efficacy Research Articles

Clinical efficacy of icotinib in lung cancer patients with differentEGFRmutation status: a meta-analysis

Icotinib is a novel and the third listed epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), which exerts a good anti-tumor efficacy on non-small cell lung cancer (NSCLC). The efficacy of EGFR-TKIs has been shown to be associated with the EGFR mutation status, especially exon 19 deletion (19Del) and exon 21 L858R mutation. Therefore, a meta-analysis was performed to assess the efficacy of icotinib in NSCLC patients harboring EGFR mutations (19Del or L858R) and wild type (19Del and L858R loci wild type). A total of 24 studies were included for comparing the objective response rate (ORR) in the EGFR wild type and mutant patients treated with icotinib. The ORRs of EGFR mutant patients (19Del or L858R) are better than those of EGFR wild type patients (OR = 7.03(5.09–9.71), P < 0.00001). The pooling ORs from 21 studies on the disease control rate (DCR) in EGFR mutant patients are better than those of EGFR wild type patients (OR = 10.54(5.72–19.43), P < 0.00001). Moreover, the ORRs of EGFR 19Del patients are better than those of EGFR L858R patients after pooling ORs of 12 studies (OR = 2.04(1.12–3.73), P = 0.019). However, there was no significant difference on DCRs of EGFR 19Del patients and those of EGFR L858R patients (OR = 2.01(0.94–4.32), P = 0.072). Our findings indicated that compared with EGFR wild type patients, EGFR mutant patients have better ORRs and DCRs after icotinib treatment; EGFR 19Del patients treated with icotinib have better ORRs than EGFR L858R patients. EGFR mutation status is a useful biomarker for the evaluation of icotinib efficacy in NSCLC patients.

A stable nanoplatform for antitumor activity using PEG-PLL-PLA triblock co-polyelectrolyte

Polyelectrolyte has been proposed as an efficient approach for various types of drug formulations. However, one drawback of using the conventional polyelectrolyte for drug delivery is its dissociation in in vivo conditions by counter ions due to the lack of self-assembling aggregation force. In this study, we reported a stable nanoplatform based on triblock co-polyelectrolyte composed of a poly(ethylene glycol), poly(l-lysine), and poly(lactic acid). These co-polyelectrolytes formed stable aggregates through the hydrophobic interaction of PLA and showed consistent particle sizes under a high salt concentration. In addition, the doxorubicin (Dox) loaded triblock co-polyelectrolyte demonstrated enhanced cellular uptake and drug cytotoxicity with a positive charge from the poly(l-lysine) layer. In vivo, the triblock aggregates exhibited intensive accumulation at the targeted tumor site for 24h with good antitumor therapeutic efficacy. Therefore, the prepared stable triblock co-polyelectrolyte may have considerable potential as a nanomedicinal platform for anticancer and multi-drug combination therapy.

Evaluation for preparation and anticancer efficacy in vitro of drug-loaded nanoerythrosomes

The objective of this study is to develop a new-type biodegradable, biocompatible curcumin-loaded nanoerythrosomes (Cur-RBC-NPs) by means of the sonication method. The size of Cur-RBC-NPs was optimized by varying drug loading parameters. The morphology, size distribution, stability, in vitro release pattern, cellular uptake of nanoparticles and in vitro anti-tumor effects were evaluated, respectively. The results showed the prepared Cur-RBC-NPs were nearly uniform spheres, with an average diameter of (245.7 ± 1.3) nm. Encapsulation efficiency (EE) and load efficiency (LE) of Cur-RBC-NPs were 50.65% ± 1.36% and 6.27% ± 0.29%. And the nanoparticles had a good sustained release property. According to the in vitro experiment, Cur-RBC-NPs were effectively taken in by tumor cells, and exhibited a significant anti-tumor effect. In conclusion, the method for preparing Cur-RBC-NPs is convenient, with a good sustained release behavior and anti-tumor efficacy, and so expected to be a new-type nano-drug delivery system in clinical practice.

Abstract B120: Characterization and combination immunotherapy treatment of an inducible autochthonous murine lung cancer model expressing human carcinoembryonic antigen (CEA) as a tumor-associated self-antigen

Abstract Previous work from our lab has demonstrated that a combination of anti-tumor antibody and an IL-2 fusion protein that exhibits extended serum half-life elicits an immune response that can effectively control a wide variety of tumor models. We have since then combined this therapeutic regimen with a vaccine exhibiting efficient lymph node trafficking that can generate an impressive population of tumor-antigen specific CD8+ T-cells but by itself does not provide good anti-tumor efficacy. The efficacy of this combination immunotherapy is further boosted by immune checkpoint blockade, leading to a robust four-component therapy: 1) anti-tumor antigen antibody; 2) IL-2 fusion protein; 3) anti-tumor antigen vaccine; 4) anti-PD-1 antibody. Although this four-pronged approach is demonstrably effective in the syngeneic subcutaneous melanoma model B16F10, we wish to test its efficacy in a more physiological model. To this end, we have turned to a model developed by the Jacks Lab, known as the KP model: an inducible lung tumor model where lentivirus-driven integration and expression of Cre is able to activate oncogenic Kras and completely remove p53 function. Because our therapeutic regimen requires a targetable tumor-associated antigen with respect to both the antibody and vaccine, we chose to induce expression of human carcinoembryonic antigen (CEA) in these tumors, as CEA has a well-studied structure and biology, and frequently expresses aberrantly in many forms of human adenocarcinomas. Additionally, our lab has previously engineered an antibody targeting CEA possessing picomolar affinity. Finally, to remove any endogenous immunological response against human CEA as a foreign antigen in our mouse system, we have crossed the KP model with a mouse model transgenic for human CEA, which in the literature has been described to have identical spatiotemporal expression of CEA as found in humans and should allow for central tolerance of this antigen. In the course of this work, we have successfully introduced human CEA into our lentivirus constructs and shown tumorigenesis by these constructs in the KP model coincides with expression of tumor-associated CEA, as detected by qPCR. On the therapeutic side, we have tailored the vaccine to successfully drive an anti-CEA CD8+ T-cell response. Performing preliminary therapeutic experiments in a transplant model of the KP tumor with our four-component therapy, we saw tumor control compared to untreated tumors. Upon interrogating the CD8+ T-cell response against CEA, we found 1-15% of CD8+ T-cells in the blood respond to CEA stimulation by intracellular cytokine staining. With regards to the lung tumor model, in the course of establishing the system we have also observed that the growth kinetics of tumors expressing CEA lags behind those tumors without CEA, even in the transgenic background. Preliminary immunophenotyping work by flow cytometry suggests that tumors with CEA seem to have a reduced myeloid-derived suppressor cell (MDSC) population and a higher CD8a+ dendritic cell (DC) population compared to tumors without CEA, suggesting that the former may have a less immunosuppressive tumor microenvironment that is better able to prime an anti-tumor CD8+ T-cell response. We will be planning to conduct therapeutic trials in the more physiological lung tumor KP model in the near future, as well as investigate the differences in the immune response with tumors expressing or lacking CEA. Citation Format: Eric F. Zhu, Kavya Rakhra, Naveen Mehta, Kelly D. Moynihan, Cary F. Opel, Darrell J. Irvine, K. Dane Wittrup. Characterization and combination immunotherapy treatment of an inducible autochthonous murine lung cancer model expressing human carcinoembryonic antigen (CEA) as a tumor-associated self-antigen. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B120.

Transarterial oily chemoembolization with lidamycin shows potent therapeutic efficacy in VX2 rabbit liver tumor.

Transarterial oily chemoembolization (TOCE) is one of the most effective approaches for the treatment of patients with hepatocellular carcinoma (HCC), who are not suitable for surgical therapy. Lidamycin (LDM), a potent antitumor antibiotic, demonstrates good antitumor efficacy in various tumor types, both in vitro and in vivo. In this study, the antitumor efficacy of LDM combined with TOCE against the rabbit VX2 tumor was assessed. A toxicity assay with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) demonstrated that a combination of LDM with lipiodol did not impair the cytotoxicity of LDM against HepG2 cells in vitro. Using TOCE in rabbit VX2 tumor models, LDM showed a more powerful inhibitory effect against the tumor and lowered the expression levels of proliferating cell nuclear antigen (PCNA), cluster of differentiation 31 (CD31), and vascular endothelial growth factor (VEGF) compared to Adriamycin (ADM); moreover, this improvement was not accompanied by an increase of hepatotoxicity as shown by alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. These results suggested that LDM combined with TOCE may be a feasible strategy in HCC therapy in the future.

A nanoparticulate drug-delivery system for 20(S)-protopanaxadiol: formulation, characterization, increased oral bioavailability and anti-tumor efficacy

As with many other hydrophobic anticancer agents, 20(S)-protopanaxadiol (PPD) has a very low oral bioavailability. In this study, a precipitation-combined ultrasonication technique was used to prepare PPD nanosuspensions. The mean particle size of the nanosuspensions was approximately 222 ± 12 nm, the drug payload achieved 50% after lyophilization and the maximum PPD concentration can reach 100 mg/ml, which is over 30 000 times the solubility of PPD in aqueous solution (3 μg/ml). After oral administration, the Cmax and AUClast values of PPD nanosuspensions were approximately 3.66-fold and 3.48-fold as those of PPD coarse suspensions, respectively. In contrast to the free drug solution, PPD nanosuspensions showed higher in vitro anti-tumor activity against HepG-2 cells (an IC50 value of 1.40 versus 5.83 μg/ml at 24 h, p < 0.01). The in vivo study in H22-tumor-bearing mice demonstrated that PPD nanosuspensions showed good anti-tumor efficacy with an inhibition rate of 79.47% at 100 mg/kg, while 50 mg/kg of cyclophosphamide was displayed as positive control, and the inhibition rate was 87.81%. Considering the highest drug payload, oral bioavailability reported so far, significant anti-tumor efficacy and excellent safety of encapsulated drugs, PPD nanosuspensions could be used in potential effective strategies for anticancer therapy; further investigation is ongoing.

Octreotide acetate-templated self-assembly Pt nanoparticles and their anti-tumor efficacy

Chain-like platinum nanoparticles, prepared using octreotide acetate as a biotemplate, have a good anti-tumor efficacy in tumor-bearing mice.

Abstract 614: Proxalutamide (GT0918), a potent androgen receptor pathway inhibitor

Abstract Elevated AR expression or mutations in tumor cells, causing resistance to first generation AR antagonist agents, are considered the main driver of castration resistant prostate cancer (CRPC). MDV3100, a more potent AR antagonist ( 5x vs bicalutamide) without residual agonism, has demonstrated excellent efficacy in CRPC patients and has been approved by FDA for treating CRPC in clinic. More recently, AR antagonists demonstrated anti-tumor activities in preclinical AR+ breast cancer models and are being tested in clinical trials. Although MDV3100 is generally well-tolerated, there is a need to eliminate the clinically observed CNS AE's ( 1% incidences of seizure) and revserse the resistance to MDV3100 in CRPC patients. Suzhou Kintor previously reported a preclinical candidate compound Proxalutamide (GT0918), a potent androgen receptor (AR) antagonist with ability to down regulate AR protein level in prostate cancer cells. In biochemical assay, GT0918 more potently inhibits androgen binding with AR's ligand binding domain than Bicalutamide (11.4x) and MDV3100(3.5x). In both hormone-sensitive (LNCaP) and CRPC (C4-2) cancer cells, GT0918 demonstrated stronger potency to block AR function of gene transcription than Bicalutamide (∼5-10) and MDV3100(2-5x) while maintaining full antagonism in CRPC cells. GT0918 impairs androgen stimulated AR translocation to cell nuclei hence blocks its binding DNA and shuts down the downstream oncogenic signaling. Moreover, GT0918 induced AR down regulation in prostate cancer cells. As the AR up-regulation remains to be the main driver of CRPC resistance, its feature of AR down regulation may enable GT0918 to retain efficacy against CRPC that have developed resistance to current AR-blockage treatments. In vitro, GT0918 not only inhibits proliferation of hormone-sensitive CaP cells, but also more potently inhibits proliferation of CRPC cells than MDV3100 (6.5x). In addition, GT0918 inhibits the growth of AR positive breast cancer cells. In contrast, GT0918 has minimum effects on the growth of AR-negative CaP cells (PC-3 and DU145), indicating it is a selective AR pathway inhibitor. In vivo, GT0918 demonstrated good anti-tumor efficacy among hormone sensitive, CRPC and AR+ breast cancer animal models with efficacious drug exposure lower than MDV3100. ADME profile was optimized for once a day dosing schedule in human to reduce drug accumulation as seen in MDV3100. IND-enabling GLP toxicology studies have been completed for GT0918, which was well-tolerated with minimum safety findings except for the effects expected from anti-androgens. Toxicokinetic studies confirmed the drug exposures in toxicology studies were significantly higher (rat: 11; dog: 25x) than the exposure required for maximum efficacy. No seizure was observed across all the animal safety studies. An IND application has been filed for starting Phase I clinical trial to test the selective AR pathway blocker GT0918 in patients. Citation Format: Youzhi Tong, Chunyun Chen, Juan Wu, Jiangtao Yang, Huihui Zhang, Xiaojun Wu, Yanmei Duan, Wei Gao, Weidong Qian, Xiaoxia Niu, Lili Mi, Chuangxing Guo. Proxalutamide (GT0918), a potent androgen receptor pathway inhibitor. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 614. doi:10.1158/1538-7445.AM2014-614

Efficacy of treatment with siRNA targeting Bcl-2 in combination with HCPT against transplanted H₂₂ hepatoma in mice

To investigate the efficacy of treatment with siRNA targeting Bcl-2 in combination with HCPT against H₂₂ hepatoma transplanted in mice. siRNA targeting Bcl-2 mRNA was successfully designed and synthesized. Then, the Bcl-2 siRNA was transfected into H₂₂ hepatoma transplanted in mice in combination with HCPT for treatment. The changes of tumor volume, body weight and survival rate were observed. Tumor tissues were processed into paraffin blocks and sections were stained with hematoxylin and eosin (HE) to investigate the morphological changes of the tumor cells. RT-polymerase chain reaction (PT-PCR) was used to assess the expression of Bcl-2 mRNA in tumors and cells. Cell cycle and apoptosis of H₂₂ hepatoma cells transplanted in mice were further determined by flow cytometry. After treatment for 21 days, the tumor volume was around (571.47 ± 67.31)mm³ in the group of siRNA in combination with HCPT, which was significant smaller than that of the groups of HCPT [(880.47 ± 107.31) mm³, P < 0.05], siRNA interfere [(1119.55 ± 158.60)mm³, P < 0.01] and saline (1357.64 ± 197.92)mm³, P < 0.01]. The median survival time of the group receiving siRNA in combination with HCPT treatment was 26 days, which was significantly longer than that of the group receiving HCPT (14 day, P < 0.05), siRNA interfere (21 day, P < 0.05) and saline (12 day, P < 0.05). Larger necrotic area, lower expression of Bcl-2 mRNA, less cells at S phase and more apoptotic cells could be obviously seen in tumor tissues in the group of siRNA in combination with HCPT treatment. Bcl-2 siRNA in combination with HCPT has good synergetic antitumor efficacy in H₂₂ hepatoma-bearing mice.

Abstract A165: Antitumor activity of mTOR kinase inhibitor CC-223 in a mouse model of prostate cancer.

Abstract CC-223 is an orally active selective mammalian target of rapamycin (mTOR) kinase inhibitor which is currently in clinical development. In biochemical assays CC-223 was highly selective to mTOR over 249 kinases. In cellular assays CC-223 inhibited both mTORC1 and mTORC2 as evidenced by inhibition of pS6RP(Ser 235/236) and pAkt(Ser 473). The current study was aimed to determine the pharmacokinetic/pharmacodynamic (PK/PD) relationship, antitumor activity, and mechanism of action of CC-223 in mice with PC3 human prostate cancer tumors. In PK/PD studies with PC3 tumor-bearing mice, CC-223 exhibited a dose-dependent inhibition mTOR pathway biomarkers, pS6RP, and pAkt, which correlated with plasma exposure. Antitumor activity of CC-223 was tested in mice with PC3 tumors of approximately 100-150 mm3 in size. CC-223 consistently exhibited dose-dependent tumor growth inhibition. The minimum dose required to obtain &amp;gt;65% tumor volume reduction compared with vehicle control was 5 mg/kg BID. In addition to showing antitumor activity in smaller tumors, CC-223 also caused the regression or growth delay of larger PC3 tumors. At 10 mg/kg BID, CC-223 caused the regression of tumors, whereas 5 and 1 mg/kg BID slowed tumor growth compared to the vehicle control. The mechanism of action of CC-223 on PC3 tumors was characterized by analyzing tumors for functional markers (proliferation, apoptosis, and blood vessel markers). The number of proliferating cells in CC-223-treated tumors was significantly reduced compared to vehicle control. A significant increase in the number of apoptotic cells and a significant decrease in blood vessel density was observed in CC-223-treated tumors. In conclusion, treatment with the mTOR kinase inhibitor CC-223 significantly inhibited PC3 prostate tumor growth. Significant inhibition of mTOR pathway markers pS6RP and pAkt in CC-223-treated tumors suggests that the observed antitumor activity of CC-223 was mediated through inhibition of both mTORC1 and mTORC2. Maintenance of &amp;gt;80% and &amp;gt;60% biomarker inhibition for pS6 and pAkt, respectively, and plasma levels greater than 0.2 μM through 8 hours twice daily confers good antitumor efficacy in PC3 tumors. Further immunohistochemical data demonstrated that the antitumor activity of CC-223 was not only due to the inhibition of tumor cell proliferation but also due to the increase in apoptosis and antiangiogenic activity of CC-223. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A165. Citation Format: Rama Krishna Narla, Sophie Peng, Jim Gamez, Jason Katz, Julius Apuy, Mehran Moghaddam, Kimberly E. Fultz, Sabita Sankar, Deborah S. Mortensen, Heather K. Raymon. Antitumor activity of mTOR kinase inhibitor CC-223 in a mouse model of prostate cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A165.

Novel multicore niosomes based on double pH-sensitive mixed micelles for Ginsenoside Rh2 delivery

In this study, we report the novel double pH-sensitive mixed micelles to fabricate multicore niosomes for drug delivery. The double pH-sensitive mixed micelles (PMM) were prepared with different pH-sensitive polymers, mPEG2000-Hz-CHEMS and mPEG2000-IS (2:1 w/w). Ginsenoside Rh2-loaded DPMM was mixed with Pluronic F-68, in the aqueous medium, and multicore niosomes were fabricated. The size of multicore niosomes were around 100–300 nm with a high encapsulation efficiency of G-Rh2. The G-Rh2-MCN could release encapsulated G-Rh2 with an accelerated rate under lower pH conditions with lower cytotoxicity and good antitumor efficacy.

Abstract 2460: Discovery of potent androgen receptor antagonists for treating CRPC and AR+ breast cancer.

Abstract Androgen Receptor (AR) antagonists have been used in clinic to treat prostate cancer. One example is bicalutamide (Casodex®), which is used along with castration to treat advanced prostate cancer. Unfortunately, the patients developed resistance to bicalutamide (alone or in combination therapy) after only 0.5-2 years of treatment, resulting in castration-resistant prostate cancer (CRPC). Elevated AR expression in tumor cells correlates with a change in the functional activity of bicalutamide from antagonist to agonist, suggesting that prostate tumors may adapt to survive on any residual agonism. MDV3100, a more potent AR antagonist (∼5x vs bicalutamide) without residual agonism, has demonstrated excellent efficacy in CRPC patients and has been approved by FDA for treating CRPC in clinic. Recently, AR antagonists demonstrated anti-tumor activities in preclinical AR+ breast cancer models. Approximately 75% of invasive breast cancers were founded to be AR+. Although MDV3100 is generally well-tolerated, there is a need to eliminate the clinically observed CNS adverse side effects (∼1% incidences of seizure). Suzhou Kintor launched a research effort looking for more potent full AR antagonists with reduced CNS drug distribution. Lead series was rapidly generated by computer-aided drug design. Designed molecules based on clinically proven thiohydantoin core were docked into AR LBD binding site and filtered with criteria of binding and ability to induce antagonism conformation. Initial optimization mainly focused on improving AR antagonism potency. Additional substitutions were introduced in the left hand side to increase binding affinity to AR whereas more extended fragment was used in the AR helix 12 region to prevent AR to adopt agonism conformation hence ensure full antagonism (which may help overcome resistance arise from residual AR agonism). Further optimization for ADME properties with focus to reduce CNS drug exposure led to discovery of several candidate compounds, after overcoming the challenge of increase polarity while maintaining/improving AR antagonism potency. GT0918 and GT0903 emerged as two of top candidates for further preclinical clinical development. Both compounds have excellent affinity with AR (4-10x tighter than MDV3100), as well as potent AR antagonism (2-5x more potent than MDV3100). They also demonstrated good anti-tumor efficacy in both hormone sensitive and CRPC animal models. In addition, both candidate compounds demonstrated anti-proliferation effects in AR positive breast cancer cell lines (MCF-7 and MDA-MB-453). With higher polar surface area (PSA), GT0918 demonstrated low CNS drug distribution and no seizure was observed in animal toxicity studies (up to 1g/kg, rat/dog). With improved ADME profile (better solubility and predicted to have less drug accumulation in patients), GT0918 is being developed for Phase I trial start. Citation Format: Youzhi Tong, Chunyun Chen, Juan Wu, Huihui Zhang, Xiaojun Wu, Yanmei Duan, Wei Gao, Xiaoxia Niu, Linglan Ma, Chuangxing Guo. Discovery of potent androgen receptor antagonists for treating CRPC and AR+ breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2460. doi:10.1158/1538-7445.AM2013-2460

Abstract 2884: Preclinical studies on tumor retention, antitumor efficacy and toxicity of thermally responsive polypeptide-based radionuclide intratumoral depot in nude mice

Abstract Despite clear advantages of brachytherapy over external beam radiotherapy, current implementations of this approach have several limitations. These include the need for general anesthesia or intravenous sedation, complicated placement procedures and the need for post -treatment re-excision for device removal. An alternative approach that circumvents these constraints would be clearly attractive. In a previous study, we demonstrated that a thermally sensitive elastin-like polypeptide (ELP) displayed increased tumor retention through a thermally triggered in-situ coacervation and delayed tumor growth through the therapeutic action of a conjugated radionuclide, 131I, over a non-thermally sensitive ELP following intratumoral (i.t.) administration. However, this “smart” radionuclide carrier did not lead to complete tumor regression and had a small effect on survival. To improve the antitumor efficacy of this thermally sensitive ELP-radionuclide conjugate (ELP-depot), we investigated the effects of three orthogonal parameters upon radionuclide retention in tumor following i.t administration: the ELP concentration, molecular weight and tyrosine content (hydrophobicity). Furthermore, using the ELP-depot optimized in the above studies, we examined the antitumor efficacy and toxicity in two human tumors (human head and neck squamous carcinoma (FaDu) and human prostate (PC-3) tumor) xenografts in nude mice. The results demonstrate that the injected concentration, the transition temperature (Tt), and the hydrophobicity are critical design parameters with significant influence over radionuclide tumor retention. A 16-fold increase in concentration from 62.5 μM to 1000 μM resulted in a 5-fold increase in retention (16% ID versus 85% ID) 7 days post-injection (p &amp;lt; 0.01, ANOVA). Decreasing the Tt (a value dependent upon the molecular weight) from 30 °C to 24 °C resulted in a 14-fold increase in tumor retention over the same time period (p &amp;lt; 0.01, ANOVA). Tyrosine content-induced the changes of ELP hydrophobicity have significantly affected the behavior of radionuclide in tumor, presenting that the tumor retention, radioactivity stability and antitumor efficacy were enhanced with the increase in the tyrosine number from 1,4 to 7. This optimized ELP depot achieved a 100% of tumor response to this radiotherapy in both tumor xenografts and no significant toxicity was found in either of tumor models. Interestingly, complete tumor regression (tumor size turned out to be zero at the end of the experiment) rate was 67% in FaDu and 77% in PC-3. Together, all our data indicates that the ELP radionuclide depot is an ideal intratumoral radionuclide carrier, because it is injectable, biocompatible, has long tumor retention and good antitumor efficacy for local radiotherapy of solid tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2884. doi:1538-7445.AM2012-2884

Abstract 2795: Safety profile and therapeutic potential in breast cancer of STX140, an original tubulin binding agent

Abstract STX-140 is an anti-tubulin binding agent which has demonstrated a good anti-tumor efficacy profile. Although the binding site on tubulin differs from other classical tubulin binders, one could anticipate the same type of safety issues with such an agent, namely neurotoxicity. In order to differentiate this compound, we evaluated its efficacy in a transgenic model of mammary cancer, its neurotoxicity potential, and its therapeutic index in a breast cancer model. STX140 efficacy was evaluated in C3(1) Tag transgenic mice which develop mammary carcinomas. In those transgenic animals, the disease progresses in a similar fashion to human breast cancer, with the development of tumors which show the same histological characteristics as the human pathology. In these mice, STX140 was able to significantly increase the survival of the animals and to suppress the emergence of metastases, whereas paclitaxel was completely inactive on both parameters. Neurotoxicity potential was assessed in a thermal hyperalgesia model in comparison with paclitaxel. Continuous oral treatment of mice with STX-140 did not induce an increase sensibility to heat as measured by the latency of paw withdrawal after a heat stimulus. However, paclitaxel increased this heat sensitivity starting after the second i.v. administration, underlying the neurotoxicity of this compound, which is observed in the clinic. Finally, in MDA-MB-231 breast cancer xenografts, two different schedules of oral administration were evaluated in order to determine the therapeutic index and PK parameters were measured in parallel to the anti-tumor efficacy. Continuous (QD) and intermittent (Monday, Wednesday, Friday; MWF) treatments were evaluated and a large panel of doses were tested. The therapeutic index was determined as the ratio of the exposure observed between the first toxic dose and first active dose. The TI for the QD schedule was 2.1 and was 1.7 for the MWF schedule, showing the potential good safety index of this compound. Taking into account the previous data reported elsewhere and new data presented here, which underline the great efficacy and safety profile of STX140, this compound is considered for further preclinical and clinical development. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2795. doi:1538-7445.AM2012-2795

Imidazopyridine derivatives as potent and selective Polo-like kinase (PLK) inhibitors

A novel class of imidazopyridine derivatives was designed as PLK1 inhibitors. Extensive SAR studies supported by molecular modeling afforded a highly potent and selective compound 36. Compound 36 demonstrated good antitumor efficacy in xenograft nude rat model.

Pharmacokinetic study of S-1

Since the first synthesis of 5-FU in 1957 fluoropyrimidines have been widely used clinically in the treatment of solid tumors. Because of good anti-tumor efficacy of 5-FU as a single agent on gastrointestinal tract tumors, many attempts have been made to develop new and superior 5-FU derivatives. Recently, S-1, a new antitumor medication based on the biochemical modulation of 5-FU, (1 M Tegafur (ftorafur, FT), 0.4 M 5-chloro-2, 4-dihydroxypyridine (gimeracil, CDHP), and 1 M potassium oxonate (oteracil, Oxo)) was developed. FT, which is a prodrug of 5-FU, plays a role as an effector. Both CDHP and Oxo, which do not have antitumor activity themselves act as modulators. CDHPcompetitively inhibits dihydropyrimidine dehydrogenase (DPD, EC 1.3.1.2), which in vitro degrades 5-FU about 180 times more effectively than uracil, leading to prolonged concentrations of 5-FU in blood. Oxo competitively inhibits pyrimidine phosphoribosyl transferase (EC 2.4.2.10), which converts 5-FU to 5fluorouridine 5’-monophosphate. Oxo is distributed primarily to the gastrointestinal tract after p.o. administration. This component of S-1 decreases the incorporation of 5-fluorouridine triphosphate into RNA in the gastrointestinal mucosa and reduces the incidence of diarrhea.

BIBF 1120: Triple Angiokinase Inhibitor with Sustained Receptor Blockade and Good Antitumor Efficacy

Inhibition of tumor angiogenesis through blockade of the vascular endothelial growth factor (VEGF) signaling pathway is a novel treatment modality in oncology. Preclinical findings suggest that long-term clinical outcomes may improve with blockade of additional proangiogenic receptor tyrosine kinases: platelet-derived growth factor receptors (PDGFR) and fibroblast growth factor receptors (FGFR). BIBF 1120 is an indolinone derivative potently blocking VEGF receptor (VEGFR), PDGFR and FGFR kinase activity in enzymatic assays (IC(50), 20-100 nmol/L). BIBF 1120 inhibits mitogen-activated protein kinase and Akt signaling pathways in three cell types contributing to angiogenesis, endothelial cells, pericytes, and smooth muscle cells, resulting in inhibition of cell proliferation (EC(50), 10-80 nmol/L) and apoptosis. In all tumor models tested thus far, including human tumor xenografts growing in nude mice and a syngeneic rat tumor model, BIBF 1120 is highly active at well-tolerated doses (25-100 mg/kg daily p.o.), as measured by magnetic resonance imaging of tumor perfusion after 3 days, reducing vessel density and vessel integrity after 5 days, and inducing profound growth inhibition. A distinct pharmacodynamic feature of BIBF 1120 in cell culture is sustained pathway inhibition (up to 32 hours after 1-hour treatment), suggesting slow receptor off-kinetics. Although BIBF 1120 is rapidly metabolized in vivo by methylester cleavage, resulting in a short mean residence time, once daily oral dosing is fully efficacious in xenograft models. These distinctive pharmacokinetic and pharmacodynamic properties may help explain clinical observations with BIBF 1120, currently entering phase III clinical development.

New unsaturated polyesters as injectable drug carriers

New unsaturated polyesters of poly(fumaric acid–glycol–sebacic acid) copolymers and poly(maleic anhydride–glycol–sebacic acid) copolymers were prepared by melt polycondensation of the corresponding mixed monomers: sebacic anhydride, fumaric acid or maleic anhydride and glycol. Methyl-methacrylate (MMA) was used as crosslinker and dimer acid was used as thinner. In vitro studies showed that those copolymers are degradable in phosphate buffer at 37 °C and poly(fumaric acid–glycol–sebacic acid) has proper drug release rate as drug carriers. The biocompatibility of poly(fumaric acid–glycol–sebacic acid) copolymers under mice skin was also evaluated; macroscopic observation and microscopic analysis demonstrated that the copolymer is biocompatible and well tolerated in vivo. The injected poly(fumaric acid–glycol–sebacic acid) [molar ratio M fumaric acid: M glycol: M sebacic acid = 1.75:2.20:0.25] containing 5% adriamycin hydrochloride (ADM) in the mice bearing Sarcoma-180 tumor exhibited a good antitumor efficacy. The volume doubling time (VDT) (18 ± 2.5 days) of the tumor growth by this treatment was longer than that (7 ± 0.9 days) by the subcutaneous injection of ADM.

Small Molecule Vascular Disrupting Agents: Potential New Drugs for Cancer Treatment

Vascular disrupting agents (VDAs) are a new class of potential anticancer drugs that selectively destroy tumor vasculature and shutdown blood supply to solid tumors, causing extensive tumor cell necrosis. VDAs target established tumor blood vessels, which are distinct from antiangiogenic agents that prevent the formation of new blood vessels. There are two types of VDAs, small molecules and ligand-directed agents. Most of the small molecule VDAs are tubulin inhibitors, including CA4P, ZD6126, AVE8062, OXi-4503, NPI-2358, MN-029 and EPC2407. The others are synthetic flavonoids including FAA and DMXAA that induce the production of local cytokines such as TNF-alpha. VDAs have shown good antitumor efficacy in animal models, especially in combination with established anticancer agents. Several VDAs, including CA4P and DMXAA, have demonstrated good safety profile as well as some promising efficacy in phase I clinical trials. Currently CA4P and DMXAA are in phase II clinical trials and AVE8062, OXi-4503, NPI-2358 and MN-029 are in phase I clinical trials. This review will focus on recent progress in the discovery and development of small molecule VDAs, including recently published patent applications and issued patents related with small molecule VDAs.

The use of molecular markers in farnesyltransferase inhibitor (FTI) therapy of breast cancer.

The hypothesis that pharmacologic inhibitors of Ras can be effective anti-cancer agents has led to the development of Farnesyltransferase inhibitors (FTIs). These agents inhibit the requisite processing of a number of cellular proteins including Ras. FTIs have shown good anti-tumor efficacy and little toxicity in preclinical models and based on these results, numerous clinical trials are currently underway to evaluate the clinical potential of these agents in patients with cancer. However, contrary to the ideas that led to their design, mechanistic studies have not confirmed that they inhibit tumors through the inhibition of Ras. FTIs inhibit the growth of a broad variety of human tumor cells in vitro and studies to date have not identified cellular characteristics that predict the antitumor efficacy of this class of agents. We have studied a panel of breast cancer cell lines that differ widely in their sensitivity to FTI in order to determine which molecular characteristics may determine sensitivity to this class of agents. In these cells we find that FTI sensitivity does not correlate with the relative expression of Ras isoforms or the inhibition of Ras processing, growth factor signaling, expression of estrogen receptor or the overexpression of growth factor receptors. Looking for other molecular correlates of FTI sensitivity we have compared the activity of farnesylprotein transferase (FPTase) among these cells and although we find no overall correlation with FTI sensitivity, we find that two cell lines with unusually low FPTase activity are sensitive. Comparing p53 genotype with FTI-sensitivity we find that although most cell lines in our panel have mutant p53, all three cell lines with wild-type p53 are quite sensitive to FTI. In fact, MCF-7 cells which have both wild-type p53 and the lowest FPTase activity are the most FTI-sensitive cell type we have ever seen. Although these studies do not identify any single molecular marker that can accurately predict FTI sensitivity in breast tumors, they highlight the potential roles of FPTase activity and p53 function for further analysis.