bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract B223: NKP-1339 synergistic activity in both in vitro and in vivo preclinical models highlights the therapeutic opportunity for NKP-1339 combination trials with a broad range of antitumor agents.
Authors: Baerga Rebecca , Cobb Jenel , Ogden Angela , Sheshbaradaran Hooshmand
Published: June 2012

Background: NKP-1339 is a novel transferrin targeted ruthenium based compound that has shown promising single agent anti-cancer activity in preclinical models and in man. The compound has a novel mechanism of action, with GRP78 down-regulation included in its target pathways. In an ongoing Phase I study, the side effects are all mild and do not include those associated with standard cytotoxics or targeted agents, suggesting that NKP-1339 could be safely combined with standard anticancer therapies. The aim of this study was to evaluate the anti-tumor effects of NKP-1339 combination with these agents.

Methods: In vitro combination studies were performed in breast, colon, lung, gastric, prostate, pancreatic and liver tumor cell lines with cisplatin, oxaliplatin, 5-FU, docetaxel, doxorubicin, gemcitabine, erlotinib or sorafenib as appropriate for that tumor type. Cells were exposed to NKP-1339 and a combination agent, both agents at their respective ED50, for 72hrs. Cytotoxicity was determined using the MTT assay and combination index (CI) values were calculated using the Chou-Talalay method. The effect of the NKP-1339 and cisplatin combination was further studied in vivo in a gastric carcinoma xenograft model.

Results: The in vitro combination studies demonstrated NKP-1339 synergism with other anti-cancer agents in varied tumor types. The CI values ranged from 0.8 (synergism) to 0.1 (strong synergism): cisplatin (CI 0.1), doxorubicin (CI 0.2), 5-FU (CI 0.3), oxaliplatin (CI 0.4), sorafenib (CI 0.5), docetaxel (CI 0.5), erlotinib (CI 0.6), gemcitabine (0.8). In vivo studies on the combination of NKP-1339 and cisplatin in gastric carcinoma xenografts showed significant (P<0.05) tumor growth delay and extended survival when compared to the single agent activity for either compound.

Conclusions: NKP-1339's novel mechanism of action and its favorable safety profile in humans suggest that it could be safely combined with standard anti-cancer therapies. The marked synergistic effects of NKP-1339 in combination with a broad range of anti-tumor agents in vitro and in vivo supports the study of this novel agent with standard anticancer therapies in Phase I combination clinical trials.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B223.
Abstract B230: NMS-P948, a potent dual FLT3/KIT inhibitor, also active on secondary resistance mutations.
Authors: Ciomei Marina , Fraietta Ivan , Cribioli Sabrina , Marsiglio Aurelio , Casero Daniele , Nesi Marcella , Donati Daniele , Isacchi Antonella , Pesenti Enrico , Galvani Arturo , Borgia Andrea Lombardi
Published: June 2012

FMS-like tyrosine kinase 3 (FLT3) and KIT are both members of the class III receptor tyrosine kinase family characterized by an autoinhibitory juxtamembrane (JM) domain that docks with the kinase domain to stabilize a catalytically inactive conformation. Therefore, mutations or deletion in this or in adjacent regions cause constitutive activation of these kinases as observed in 30% of AML patients for FLT3 and in 70% of adult GIST and a subset of melanoma patients for KIT.

NMS-P948 is an alkoxy-indazole derivative potent dual inhibitor of FLT3 and KIT (IC50 26 and 89 nM, respectively), active also against FLT3 and KIT mutations that confer secondary resistance, such as the gatekeeper mutation T670I of KIT.

It is a very selective compound, resulting, when tested on a panel of more than 150 human tumor cell lines, strongly active only on cell lines whose proliferation is driven by one of these two kinases (for FLT3: Eol-1, IC50= 8 nM; MV-4–11, IC50= 8 nM; MOLM-13, IC50= 18 nM and for KIT: GIST-430 IC50= 7 nM and GIST-882 IC50= 99 nM). Mechanism of action is demonstrated on both kinases, with activating and resistance mutations, at low nanomolar concentrations.

NMS-P948 has good oral bioavailability in rodents. Antitumor efficacy is observed at as low as 10 mg/kg in xenograft models and no toxicity in terms of body weight loss was observed up to 60 mg/kg.

In disseminated human AML MOLM-13 model (FLT3-ITD) NMS-P948 produces a very prolonged survival of treated mice (T/C= 390 at 60 mg/kg OS daily × 10) and this antitumor efficacy results superior to that of quizartinib administered with the same schedule at the MTD (T/C= 207 at 40 mg/kg).

In conclusion, NMS-P948 is a promising dual inhibitor of mutated FLT3 and KIT with good in vitro and in vivo pharmacological and pharmacokinetic characteristics and with the potential to act also on patients that developed resistance to first line therapies.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B230.
Abstract B231: Potent in vivo activity of the Aurora kinase inhibitor ABT-348 in a broad spectrum of histological types: Evaluation of efficacy, dosing/scheduling, and PK/PD.
Authors: Donawho Cherrie K. , Montgomery Debra , Rodriguez Luis E. , Wang Yi-Chun , Ellis Paul E. , Kaleta Lance , Bukofzer Gail , Bouska Jennifer , Clarin Jerry , Schlessinger Sally , Wang Baole , Glaser Keith , Michaelides Mike , Albert Daniel , Tse Chris , Frost David J. , Palma Joann P.
Published: June 2012

The Aurora kinases are a family of serine/threonine kinases that mediate multiple essential functions in cell division. Aurora A depletion results in accumulation of cells in the G2/M phase and apoptosis. Inhibition of Aurora B/C results in abnormal cell division, polyploidy, followed by apoptosis, therefore, Aurora kinases present an attractive target for chemotherapy. Cells treated with aurora inhibitors enter mitosis with normal kinetics but fail to undergo cytokinesis due to a disruption of the mitotic spindle checkpoint. ABT-348 is a novel adenosine triphosphate (ATP)-competitive inhibitor of Aurora A, Aurora B, and Aurora C (Enzyme IC50 A=116, B=5, C= 1 nM) and a potent inhibitor of all members of the VEGF and PDGF family of receptor tyrosine kinases (RTK). Here we demonstrate profound in vivo efficacy (with regressions) in a broad spectrum of histological types (breast, colon, NSCLC, HNSCC, melanoma, ovarian, pancreatic, prostate, leukemia, lymphoma and renal; 50–94% TGI, tumor growth inhibition). The treatment was well tolerated with no animal health concerns observed. In addition, ABT-348 was also efficacious in tumor xenografts overexpressing P-gp and provided significant in vivo efficacy in comparison to competitor compounds in colon, NSCLC and ovarian xenograft models. Various dosing schemes to achieve optimal efficacy (IV, OMP and PO) were investigated. The anti-tumor efficacy of ABT-348 was not affected by the route of administration. Similar efficacy was achieved by IV, OMP or PO administration, once weekly in a dose-dependent manner. Pharmacokinetic/pharmacodynamic biomarker analysis in select tumor xenograft models were evaluated by phospho-H3 (an Aurora B substrate, proliferation marker) and cleaved caspase-3 (apoptosis marker) by IHC at various timepoints post single dose (6 hr to 9 days). Significant levels of ABT-348 were detected in the plasma and tumor. A general decrease in proliferation and increase in apoptosis consistent with the mechanism of action was observed and coincide with the potent in vivo efficacy in xenograft models. Overall, ABT-348 is a potent, oral Aurora kinase inhibitor, demonstrating robust in vitro and in vivo antitumor activity with a good safety profile that warrants investigation in the clinic. ABT-348, is currently undergoing Phase I clinical trials in both solid and hematologic malignancies.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B231.
Abstract B240: Combined gefitinib and API-2 induced interaction of DNA-PK with EGFR and Akt, leading to impaired DNA-PK-mediated DNA repair and increased autophagy.
Authors: Kang Khong Bee , Zhu Congju , Wong Yin Ling , Yong Sook Kwin , Wong Meng Cheong
Published: June 2012

Resistance to epidermal growth factor receptor (EGFR) inhibitors and pro-apoptotic agents frequently occurs in malignant glioma due to excessive stimulation of growth factor receptors (eg. EGFR) and up-regulation of PI3K/Akt pathway. We aimed to overcome resistance of glioblastoma cells to gefitinib (an EGFR inhibitor) with API-2 (a selective Akt inhibitor) by increasing autophagy cell death. We investigated whether combined gefitinib and API-2 induced interaction of DNA-PK with EGFR and Akt, leading to impaired DNA-protein kinase (DNA-PK)-mediated DNA repair and autophagy.

Methods: U251MG, MO59J (DNA-PKcs-deficient) and MO59K (DNA-PKcs-proficient) cells treated with gefitinib, API-2 or both for 72 hours were analyzed by cell viability (MTT assay) and autophagy (FACS of acridine orange staining and LC3 expression) assays. U251MG cells treated with gefitinib and API-2 were assayed for nuclear expression of phosphorylated and native DNA-PKcs, Akt and EGFR, as well as DNA repair activity (immunostaining of γ-H2AX, a marker of DNA damage). Interaction of DNA-PK and EGFR/Akt in gefitinib and API-2-treated cells were analyzed by proximity ligation assay.

Findings: Combined gefitinib and API-2 significantly reduced viability of U251MG and MO59J cells (but not MO59K cells), compared with gefitinib alone. Single treatments of gefitinib and API-2 increased acridine orange staining and LC3-II expression in U251MG cells, with further increase by combined gefitinib and API-2. Increased acridine orange staining by combined gefitinib and API-2 was greater in MO59J than MO59K cells. In U251MG cells, combined gefitinib and API-2 significantly inhibited nuclear phosphorylation of DNA-PKcs (S2056), EGFR (T1173) and Akt (S473), compared with single therapies. Gefitinib and API-2 independently impaired DNA repair (time-dependent increase of γ-H2AX immunostaining) of U251MG cells, with further inhibition by combined gefitinib and API-2. There was an increased binding of DNA-PKcs with EGFR and Akt following combined gefitinib and API-2 treatment (compared to single agents) in U251MG cells.

Conclusion: Our findings reveal that API-2 enhances chemosensitivity of gefitinib by inducing interaction of DNA-PKcs with EGFR and Akt, leading to impaired DNA-PK-mediated DNA repair and induction of autophagic cell death.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B240.
Abstract B245: Synergistic antiproliferative effects of the P21-activated kinase (PAK) inhibitor, PF-03758309, and standard-of-care agents in colorectal cancer models.
Authors: McPhillips Kelly L. , Pitts Todd M. , Im Eun Kyung , Spreafico Anna , Tan Aik Choon , Tentler John J. , Arcaroli John J. , Pierce Erica L. , Murray Brion W. , Eckhardt S Gail
Published: June 2012

Background: The p21-activated kinase (PAK) family of serine/threonine kinases is overexpressed in multiple cancer types including breast, ovarian, colorectal, thyroid, and pancreatic. The two groups of PAK proteins, Group I (PAK 1–3) and Group II (PAK 4–6), are critical mediators of cell survival, motility, mitosis, transcription, and translation. The goal of this study was to assess the efficacy of a PAK inhibitor, PF-03758309, with irinotecan in colorectal cancer (CRC).

Methods: A panel of 27 colorectal cancer (CRC) cell lines were exposed to increasing doses of PF-03758309 (0.015–1 μM) for 72 hours and analyzed for inhibition of proliferation using the sulforhodamine B (SRB) assay. Cell lines were designated sensitive (S), intermediate (I), or resistant (R) based on IC50's < 0.125 μM, ≥ 0.125 and ≤ 1 μM, or > 1 μM, respectively. Two sensitive and two resistant cell lines were exposed to three different concentrations of either the PAKi, irinotecan or all possible combinations. Proliferation was assessed by the SRB assay and synergy was calculated using the Calcusyn software. Apoptosis was also assessed using the luminescent Caspase 3/7 assay. Athymic nude mice were injected with primary patient derived explants. Once the tumors reached 200–300mm3 the mice were dosed with PF-03758309, irinotecan, or cetuximab or the combination. Tumors were measured twice weekly and growth curves were analyzed.

Results: Synergy was observed in both PF-03758309 sensitive and resistant cell lines, though the greatest synergy was seen in one of the more sensitive lines. Apoptosis was also increased in the combination when compared to the single agents. Of the explants treated, one of them demonstrated a synergistic/super-additive effect when dosed with the combination of irinotecan. One of the explants also demonstrated an added benefit with the combination of PF-03758309 and cetuximab. Further investigation into the differential sensitivities seen with PF-03758309 revealed that the more resistant CRC cell lines had higher expression of MDR1. When this was modulated either by shRNA knockdown or by addition of verapamil, we saw a shift to a more sensitive phenotype.

Conclusions: The combination of the PAKi, PF-03758309 with irinotecan resulted in synergistic anti-proliferative effectsand apoptosis in CRC cell lines regardless of sensitivity. Similar effects were observed in patient-derived CRC explants with PF-03758309 and standard of care agents.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B245.
Abstract B35: Hyaluronan (HA) accumulation in tumors predicts response to pegylated rHuPH20 hyaluronidase (PEGPH20) in human tumors: A biomarker strategy.
Authors: Jiang Ping , Ramanathan Ramesh , Infante Jeffrey , Thompson Curts B. , Maneval Daniel C. , Dychter Samuel , Frost Gregory I. , Shepard Michael H.
Published: June 2012

Increasing evidence suggests that the tumor microenvironment (TME) is a potential source of novel anti-tumor targets. Extracellular matrix components in the TME include the matrix glycosaminoglycan, hyaluronan (HA), which accumulates in 20–30% of solid tumors. HA functions to increase water content of HA-rich stroma, thereby creating high tumor interstitial fluid pressure (IFP) characteristic of many tumors. Cells engineered to overexpress hyaluronan synthase form tumors more readily in mouse models, and HA accumulation has been associated with disease progression and poor prognosis in human cancers. Enzymatic degradation of HA with hyaluronidase can reduce IFP and facilitate delivery of anti-tumor agents. We have previously presented data that demonstrate the therapeutic potential of PEGPH20 in tumor xenografts derived from a spectrum of human malignancies. Here we highlight the utility of HA detection methods that use aggrecan-derived HA binding region (HABR). Accumulation of HA was measured in tumor tissues from 14 different xenografts and compared with anti-tumor activity of PEGPH20. When cell line-derived tumors were classified according to HABR staining intensity as HA+1,2,3 (low to high staining), the anti-tumor activity of PEGPH20 correlated with higher accumulation of HA in tumor specimens (r=0.8). To more rigorously test the hypothesis that HA-depletion is an effective candidate therapeutic approach for cancer, we utilized non-small cell lung cancer (SCC) patient tumor explants which were characterized for HA accumulation in advance of implantation into immunodeficient mice. Three SCC explants (HA+1,2,3) were treated with PEGPH20 and tumor growth was measured over a 2-week interval. Tumor growth inhibition corresponded to HA accumulation status, with the most dramatic reduction (97%; 4/10 regressions) observed in the HA+3 SCC explants. We have extended this work and detected tumor HA in pre- and post-treatment tumor biopsies collected from two patients enrolled in a Phase 1 study with PEGPH20. In both sets of specimens, a reduction in HA accumulation was demonstrated following PEGPH20 treatment. These results provide a rationale to assess tumor HA staining as a promising biomarker for clinical investigation with PEGPH20 for the treatment of solid tumors.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B35.
Abstract B47: EGCG induces apoptosis and inhibits proliferation of nasopharyngeal carcinoma cells in vitro and in vivo.
Authors: Chen Jen-Yang
Published: June 2012

(−)-Epigallocatechin-3-gallate (EGCG), a major green tea catechin, can effectively inhibit proliferation of a variety of tumor cells and has been considered as a chemopreventive agent for cancers. In this study, EGCG was tested on the EBV latently-infected nasopharyngeal carcinoma (NPC) cells line, NA, which corresponds to the in vivo situation in NPC patient. Treatment of EGCG induces growth arrest in the S phase of cell cycle in NA cells. In vitro spheroid formation assay indicated that EGCG can induce growth inhibition in NA cell at relative low concentration (CC50=2 μM). At higher concentration (>25 μM), EGCG induces cellular DNA breakage and apoptosis via caspase activation. Moreover, cells exhibited reduction in migration and invasiveness after EGCG treatment. The expression of matrix metalloproteinases (MMP)-2 and MMP-9 was reduced after EGCG treatment. In a mice xenograft model with NA cells inoculation, oral administration of EGCG was able to inhibit the proliferation of tumors in vivo. These results indicate that EGCG is able to inhibit proliferation even at low concentration and can further induce apoptosis of NPC cells at high concentration, which make EGCG a promising candidate for chemoprevention of NPC.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B47.
Abstract B53: Multicenter phase Ib study of the safety and efficacy of palifosfamide plus carboplatin/etoposide (PaCE) in patients with small cell lung cancer or other selected cancers.
Authors: Harb Wael A. , Govindan Ramaswamy , Fisher William B. , Buck Jill Y. , Lewis Jonathan J. , Youssoufian Hagop , Einhorn Lawrence H.
Published: June 2012

Palifosfamide (Pa) is a novel DNA cross linker molecule that consists of the active anti-tumor metabolite of ifosfamide (I). Potential advantages over I include the abrogation of I-metabolite related toxicities, increased activity by virtue of increased dose delivery over time, and overcoming resistance mediated by aldehyde dehydrogenase (ALDH) overexpression. ALDH overexpression is associated with cancer cell stem-like potential in several tumor types. Pa has broad activity in vitro and in vivo preclinical models and has shown early activity in humans. A previous randomized study evaluating the addition of I to cisplatin and etoposide (E) in small cell lung cancer (SCLC) demonstrated improved survival, but with disabling increase in toxicity with the three-drug combination. We hypothesized that the substitution of Pa for I could increase the therapeutic advantage of a similar three-drug regimen. We initiated a multicenter phase I, open-label, dose-escalation study assessing the safety and efficacy of Pa in combination with carboplatin and E (PaCE regimen) in SCLC and in other cancers in which C+E is considered an appropriate therapeutic option. Tumor responses were assessed by RECIST 1.1 and relevant tumor markers. A total of 15 patients (8 females and 7 males) have been treated to date: 5 with SCLC, 2 with NSCLC, 2 with ovarian, 1 with testicular and 5 with other cancers. Serious adverse events have been reported in six patients, including, thrombocytopenia (4), leukopenia (2), and neutropenia (2). The maximum tolerated dose of Pa was determined to be 130 mg/m2 when administered in combination with E 90 mg/m2 and C AUC4. The dose limiting toxicity was neutropenic fever. To date, two radiological partial responses in five patients with SCLC and one complete response assessed by tumor markers in a patient with testicular cancer have been noted.

Conclusion: This study is ongoing, and an additional cohort evaluating Pa 130 mg/m2 in combination with E 100 mg/m2 and C AUC 4 is being evaluated. Further clinical data will be presented. The PaCE combination appears to be tolerable and has demonstrated clinical activity. Based on these data, a confirmatory study in SCLC is planned.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B53.
Abstract B55: A study of REOLYSIN in combination with gemcitabine in patients with advanced pancreatic adenocarcinoma.
Authors: Mita Monica M. , Wang Yubao , Sarantopoulos John , Vemulapalli Sushma , George Benjamin , Mita Alain , Coffey Mattew , Gill George , Mahaligam Devaligam
Published: June 2012

Background: Pancreatic cancer (Pca) continues to have a dismal prognosis and very little progress has been made in finding new efficacious treatments. Oncolytic viruses have demonstrated cytotoxic effect in several tumor xenografts, particularly in cells with RAS pathway activation. REOLYSIN (Reovirus serotype 3) has shown extensive antitumor activity in preclinical models, as well as synergistic activity with cytotoxics including gemcitabine in various cancers. Several phase 1 and 2 clinical trials demonstrated tolerability and promising activity of REOLYSIN administered as a single agent in patients with solid tumors. Due to the high frequency of Kras pathway activation in Pca, we hypothesized that REOLYSIN may enhance the anticancer activity of chemotherapy in this tumor type. Therefore, this study was initiated to test the safety and efficacy of a combination of REOLYSIN with gemcitabine in previously untreated patients with Pca.

Methods: Patients with diagnosis of chemotherapy-naïve, surgically unresectable or metastatic Pca are eligible for the study. The primary objective is Clinical Benefit Rate (CBR=CR+PR+SD≥12 weeks). Secondary objectives include progression-free survival (PFS), toxicity, tolerability as well as pharmacokinetics (PK) and pharmacodynamics (PD). Patients are treated with gemcitabine at 800 mg/m2 day 1 and 8, and REOLYSIN administered IV at day 1, 2 and 8, 9. Tumor assessment is performed every 2 cycles (6 weeks). A two stage design is used for this study. In stage 1 at least 3/17 patients must achieve CBR in order to proceed to stage 2.

Results: Fourteen patients were enrolled in the study and 10 are evaluable for efficacy. Age ranged from 48 to 82 years, mean 67 years. All patients except one reported symptomatic improvement. No CR were reported. Two patients have SD for ≥36 weeks and one patient continues on study with SD at 39 weeks. An additional patient had an unconfirmed PR of less than 6 weeks. Six patients had SD ≥ 12 weeks. The treatment was well tolerated with common non-hematological toxicities including grade 1 fever, chills, nausea and vomiting. Only two patients had grade 3 neutropenia lasting 1–2 days. No other grade 3 toxicities were seen.

Conclusion: The endpoint for the first stage of the study (≥3 CBR in the first 17 patients) has been reached and therefore enrollment will continue. REOLYSIN in combination with gemcitabine has demonstrated clinical benefit in patients with unresectable Pca with a tolerable toxicity profile.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B55.
Abstract B57: Cabozantinib (XL184) reduces pain symptoms in patients (pts) with castration-resistant prostate cancer (CRPC) and bone metastases: Results from a phase 2 nonrandomized expansion cohort.
Authors: Basch Ethan , Bennett Antonia V. , Scher Howard I.
Published: June 2012

Background: Cabozantinib is a potent inhibitor of MET and VEGFR2. Cabozantinib treatment (100 mg qd) of CRPC pts in a Phase 2 randomized discontinuation trial resulted in high rates of both disease control per RECIST and resolution of bone lesions on bone scans. In addition, the majority of pts with bone metastases and pain at baseline experienced pain improvement per post-hoc investigator survey. Based on these data, a non-randomized expansion cohort was initiated for CRPC pts that included prospective evaluation of changes in pain and analgesic use.

Methods: Eligible pts had CRPC metastatic to the bone and had progressed on prior docetaxel therapy. Pain at baseline was not required for study entry. Cabozantinib was administered open label at 100 mg free base equivalent qd, and pain and analgesic use were evaluated daily over 7-day assessment intervals at baseline and during Weeks 3, 6, 12, and every 6 weeks thereafter. Using an interactive voice-response system (IVRS) questionnaire, pts rated pain at its worst over the prior 24 hours on a scale of 0–10 (0=no pain, 10=pain as bad as you can imagine), and interference with sleep and daily activity caused by pain using items from the Brief Pain Inventory. Pts also rated pain at its worst relative to the most recent prior assessment. Daily analgesic use was self-reported by pt diary. Of 100 planned patients, 51 have been enrolled and are evaluable for pain changes in this interim analysis.

Results: For the 51 enrolled pts with a minimum of 6 weeks of follow-up, evaluable data were obtained for 183/201 (91%) assessment intervals. Changes in average worst pain are summarized in Table 1.

Among the 23 pts that had average daily worst pain at baseline ≥4, 20 reported regular use of narcotic analgesics during the baseline assessment interval. Changes in sleep and daily activity, as assessed by pain interference questions, were generally consistent with the effects observed in pain.

Conclusions: Docetaxel-pre-treated CRPC pts with bone metastases treated with cabozantinib completed IVRS pain questionnaires with a high rate of compliance (>90%) in this prospective analysis. High rates of pain reduction that was often accompanied by a concomitant decrease in narcotic use were observed in pts with baseline pain, consistent with prior retrospective analyses.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B57.
Abstract B66: PI3 kinase inhibitor enhances the efficacy of BO-1509 by suppressing MRN complex in lung cancer xenografted mice.
Authors: Sanjiv Kumar
Published: June 2012

Lung cancer is the most common cause of cancer-related death in men and women. Incidence rate of lung cancer is keep increasing year after year. Lot of progress has been made in field of lung cancer therapy to prolong lifespan of patients, but it is still inadequate. In our previous study, novel alkylating agent BO-1012 in combination with arsenic trioxide shown to have very good therapeutic efficacy in lung cancer H460 Xenografted mice. Meanwhile, we also observed activation of survival and DNA repair protein molecules in cells treated with BO-1012. In further development of drug up on modification in functional group of BO-1012, we observed enhanced lethal effect of BO-1509 in lung cancer cells. To overcome activation of survival and DNA repair protein we combined BO-1509 with PI3 kinase inhibitor LY294002. Synergism being found between two drugs in several lung cancer cells like H460, CL-1-5, CL-25 and CL-83 in culture. Furtherome, alone at doses of 5 mg/kg and 10 mg/kg BO-1509 by iv for five times reduce tumor burden 50% and 70% in H460 and CL-1-5 xenografted mice respectively. But when it combined with PI3 kinase inhibitor (LY294002) 40 mg/kg injected by ip for 10 times, tumor burden reduced 85% in H460 and 86% in CL-1-5 xenografted mice. Initial finding suggests that synergism between BO-1509 and PI3 kinase inhibitor may be due to inhibitory effect of PI3 kinase on Mre11 and Nbs1 proteins of MRN complex which play important role in homologous repair pathway. Mre11 and Nbs1 protein were found to be elevated upon treated with of BO-1509 in H460 cells. PI3 kinase inhibitor also prevents BO-1509 activated nuclear localization of Rad51 in H460 and CL-1-5 cells which is confirmed by using confocal microscopy. Based on H2AX foci formation assay, half of double strand break (DSB) in cell induced by BO-1509 get repaired by 72 h, while cells treated in combination of BO-1509 with PI3 kinase inhibitor still maintain DSB damage, which may enhance the lethal effect of BO-1509 to H460 and CL-15 cell. Complete blood profile, biochemical enzyme analysis and histopathology of major organ suggest no significant toxicity in mice treated with BO-1509 alone or in combination with PI3 kinase inhibitor.

In conclusion the combination with PI3 inhibitor increases the efficacy of BO-1509 by suppressing the DNA repair and survival factor.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B66.
Abstract B77: KRAS mutational status impact progression-free survival of patients treated with platinum-based chemotherapy in NSCLC.
Authors: Marabese Mirko , Rulli Eliana , Bettini Anna , Garassino Marina C. , Longo Flavia , Moscetti Luca , Pavese Ida , Lauricella Calogero , Broggini Massimo , Farina Gabriella
Published: June 2012

Background: KRAS mutations in NSCLC are supposed to indicate a poor prognosis and poor response to anticancer treatment. However, such evidence is only drawn from retrospective series giving controversial results. Moreover, it is possible that the various KRAS mutations differently affects prognosis, carcinogenesis and drug response as demonstrated in preclinical setting. Aim of this study is to prospectively assess the prognostic value of KRAS mutations in NSCLC patients treated with a first line platinum containing regimen. This is a properly planned ancillary study within the TAILOR trial (NCT00637910) which is mainly focused on the second line.

Methods: Tissue and blood samples were collected at diagnosis in the whole cohort of registered patients. KRAS status was centrally determined with standard direct sequencing and KRAS genotype was assessed by real time PCR. The primary hypothesis is a difference in PFS according to KRAS mutational status; the impact of the three more frequent KRAS substitutions (G12C, G12V, and G12D) was also explored. The analysis was planned at occurrence of 200 events (HR≥1.49, power 80%, 2-tailed alpha 10%), in a Cox model adjusting for Performance Status and radical surgery.

Results: Out of 565 patients registered, 341 (60.5%) were evaluable for KRAS and 85(25%) were mutated.

At a median follow-up of 17 months KRAS mutated patients showed a statistically significant worse PFS (HR 1.42 95%CI 1.06–1.94; p=0.02). No differences among doublets were observed in KRAS mutated patients. The most frequent KRAS mutations were: G12C (36.4%), G12V (21.1%), G12D (16.4%), others (25.9%). Prognostic differences among variants are observed. Final genotype analyses are ongoing.

Conclusions: This is the first prospective, pre-planned and adequately sized evaluation of KRAS in NSCLC. Patients mutated for KRAS seem to have a higher risk of progressing. These results suggest that KRAS mutation epidemiology in this setting highly differs from that of colon cancer. Clinical data suggest that tailored strategies for these patients are warranted and our preclinical studies will help in clarifying the molecular mechanisms.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B77.
Abstract B82: High frequency of hypermethylation at the 14-3-3 sigma to gene silencing in breast cancer.
Authors: Joaquina Martinez-Galan , Ramon Delgado J. , Blanca Torres-Torres , Arancha Gonzalez-Vicente , Jesus Soberino , Cynthia Gonzalez-Rivas , Julia Vozmediano
Published: June 2012

Background: Expression of 14-3-3 sigma is induced in response to DNA damage, and causes cells to arrest in G(2). Hypermethylation of CpG islands located in the promoter regions of tumor suppressor genes is now firmly established as an important mechanism for gene inactivation. Objetive: To study the relation of 14-3-3 sigma gene promoter hypermethylation and its transcription expression levels in sporadic breast carcinogenesis.

Material and Methods:This is a prospective study we quantified methylation levels of promoter 14-3-3 gene in 107 women with breast cancer and 108 control subjects by Real Time QMS-PCR SYBR green and analyzed association with prognostics factor in breast cancer.

Results: Median age was 58 years (32-88); 69% were postmenopausal women. Nodal involvement N0; 63%, N1;30%, N2;7%), tumor size (T1;58%, T2;35%, T3;4%, T4;4%) and grade G1; 20%, G2;37%, G3;30%). The methylation of 14-3-3σ were 60% of sporadic breast cancer patients and were 34% of normal breast (p=0.0047). The methylation of 14-3-3σ gene in serum was markedly related with T3-4 stage (p<0.05), nodal positive status (p<0.05) and poor outcome. With a median follow up 6 years we saw more probability of developing distance metastasis in patients with methylation 14-3-3σ (p>0.05). Conclusions: The recent identification of novel 14-3-3sigma-associated proteins by a targeted proteomics approach implies that 14-3-3sigma regulates diverse cellular processes, which may become deregulated after silencing of 14-3-3sigma expression in cancer cells. Therefore, it is possible that loss of σ expression contributes to malignant transformation by impairing the G2 cell cycle checkpoint function, thus allowing an accumulation of genetic defects. Perhaps in the detection of CpG methylation of 14-3-3σ may be used for diagnostic and prognostic purposes

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B82.
Abstract B84: HCI-2528 is a potent inhibitor of LSD1 with improved druglike characteristics.
Authors: Stephens Bret J. , Sorna Venkataswamy , Theisen Emily , Vankayalapati Hariprasad , Warner Steven , Bearss David , Sharma Sunil
Published: June 2012

Lysine Specific Demethylase 1 (LSD1/KDM1A) plays an important role in the regulation of histone methylation at lysine residues, and is currently being validated as an attractive therapeutic target for many diseases, particularly for multiple forms of cancer. Methylation of lysine residues on histones can signal transcriptional activation or repression depending on the specific residue involved. H3K4me2 is a transcription-activating chromatin mark at gene promoters, and demethylation of this mark by LSD1 is thought to prevent expression of tumor suppressor genes important in human cancer. In contrast, methylation of H3K9 is a repressive mark and LSD1 activity has been shown to upregulate tumor promoting pathways. Thus, LSD1 is emerging as an important target for the development of specific inhibitors as a new class of antitumor drugs. Several LSD1 inhibitors have been reported, but they have shown poor selectivity and/or pharmacological properties, making further exploration of LSD1 biology difficult. We previously reported the identification of CIT-0665, an LSD1 inhibitor identified through a virtual screening effort in our lab. Evaluation of the structure activity relationships of multiple analogs of our LSD1 inhibitor led to the identification of HCI-2528, which is more potent and exhibits improved drug like properties. Using a cell viability assay, a large panel of cancer cell lines was tested for sensitivity to HCI-2528. In addition to the well-documented sensitivity of breast cancer cell lines, we also found that Ewing's sarcoma cell lines are uniquely sensitive to LSD-1 inhibition. We are currently engaged in a bioinformatic effort to determine possible mechanisms of sensitivity from our studies, and performing xenograft studies in mice. In conclusion, HCI-2528 is a novel LSD1 inhibitor with activity in biochemical and cell-based assays.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B84.
Abstract B97: Microarray analysis in ependymomas, astrocytomas, and medulloblastomas: Identification of potentially related metabolic pathways.
Authors: Perez-Gonzalez Oscar , Cardenas-Cardos Rocio , Rivera-Luna Roberto , Macias-Vega Miguel
Published: June 2012

Purpose: Primary Central Nervous System Tumors (PCNST) are the most frequent solid neoplasias in childhood, in particular those derived from astrocytes, aracnoids and ependimum. The prognostic criteria is based on the anatomic localization, tumor size and surgical accesibility for resection. Nevertheless, this criteria is not enough to predict a therapeutic success in all patientes, either knows with exactitude the implied underlying biological process in paediatric cerebral tumors. The goals of this research are to identify gene expression profiles and integrate metabolic pathways potentialy related to each histological subtype.

Methods: We included neoplastic tissue samples from pediatric patients with ependymomas, astrocytomas y medulloblastomas treated at the National Institute of Pediatics, Mexico. Diagnostic approach and treatment protocols were those stablished by the Pediatric Oncology Service considering only those patients with a signed consent. We purified total RNA from these samples using RNAeasy mini kit (Qiagen), considering those samples with 8 or more RIN (RNA Integrity Number) useful for microarray hybridization on the GeneChip® Human Gene 1.0 ST Array (Affymetrix). Statistic analysis was performed with Affymetrix Expression Console and Partek's Genomics Suite. We also used the Database for Annotation, Visualition and Intgrated Discovery (DAVID, Bioinformatics Resources v6.7) for data minning in order to identify metabolic pathways potentialy related to each histological subtype with the differential gene expression results.

Results: We considered all microarrays that showed good correlation (index 0.8 to 1.0) for the statistical analysis. We found a list of genes differentially expressed according to the hystologic subtype (ependymomas, astrocytomas and medulloblastomas), and then we integrated the metabolic pathways apparently related to differentially expressed genes with DAVID. Details of these results will be presented at the meeting.

Conclusion: These results show that gene expression profiles may clearly differentiate ependymomas, astrocytomas and medulloblastomas according to their histological subtype. Differential gene expression profiles in these PCNST are being analyzed as a diagnostic tool in order to provide a more accurate allocation criteria for antineoplastic treatments based not only on their own genomic profiles but in the neoplastic behavior potentially related to the metabolic pathways results.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B97.
Abstract C134: Herceptin-targeted siRNA nanoparticles inhibit the growth Her2-positive breast cancer tumors in vivo.
Authors: Zuckerman Jonathan E. , Han Han , Medrano Leonard , Choi Chung Hang J. , Davis Mark E.
Published: June 2012

We have recently demonstrated the feasibility of using targeted, polymer-based siRNA nanoparticles in the clinic1. This delivery system involved the use of the human protein transferrin (Tf) that is displayed on the surface of the nanoparticles to engage cancer cell surface, transferrin receptors (TfR). Here, we demonstrate the modular nature of this siRNA delivery system by tailoring both the targeting agent and siRNA component of the nanoparticle to Her2 positive breast cancers. Specifically, we show that the siRNA nanoparticle delivery system can be modified to include an antibody targeting agent (Herceptin) without any significant alteration to size, charge, and pharmacokinetic behavior. We also show that in vivo treatment of Her2 positive breast cancer tumor xenografts with Herceptin-targeted nanoparticles containing siRNA against Her2 results in a more robust anti-tumor response than either Herceptin alone or Herceptin-targeted nanoparticles containing control siRNA. These data demonstrate how nanoparticles containing the combination of antibodies and siRNA can be used to achieve enhanced therapeutic treatment against clinically validated cancer targets.

References:

1. Davis, M.E. et al. Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles. Nature 464, 1067–1070 (2010).

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C134.
Abstract C151: Maspin is regulated by the alternative NF-κB subunit in androgen-insensitive prostate cancer cell lines.
Authors: Guo Feng
Published: June 2012

Dysregulation of Maspin expression and constitutive activation of NF-κB subunits are important events in tumorigenesis of prostate cancer. Recent finding points that RelB, which contributes to the alternative NF-κB activity, interferes with carcinogenesis in the prostate. We report here, that both the classical (predominantly p50/RelA heterodimers) and the alternative NF-κB activities (p52/RelB heterodimers) are constitutively present in androgen-insensitive human prostate cancer cells. An inverse relationship of Maspin and RelB expression is observed in prostate cancer tissues at the later stage. TNF-α signaling triggers the nuclear accumulation of RelB and the concomitant reduction of Maspin expression in a time-dependent manner. In addition, the proteasome inhibitor-induced Maspin expression is accompanied by the reduction of RelB expression. A successful depletion of RelB expression, but not RelA expression, induces Maspin expression. RelB-deficiency abrogates the proteasome inhibitor-induced Maspin expression. Moreover, we demonstrate that the enforced expression of RelB protein in prostate cancer cells inhibits Maspin expression. We propose that RelB is an essential molecule controlling the endogenous and the proteasome inhibitor-induced Maspin expression. Developing a RelB-targeted therapeutic intervention, which might be coupled with the induction of a tumor suppressor Maspin, is valuable in treating advanced, metastatic prostate cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C151.
Abstract C165: Breast cancer, statins, and 3-D cell culture.
Authors: Mullen Peter J. , Goard Carolyn A. , Wasylishen Amanda R. , Pandyra Aleksandra , Penn Linda Z.
Published: June 2012

Statins are widely used to lower serum cholesterol levels. They act by inhibiting hydroxymethylglutaryl coenzyme A reductase (HMGCR), the rate-limiting step in the mevalonate pathway. Recent work also shows that statins could be used as anticancer therapeutics, particularly in breast cancer. This study presents a preliminary rationale for the use of statins as a therapy in breast cancer.

We characterized a panel of breast cancer cell lines for sensitivity to fluvastatin, using proliferation and cell-death assays. We also screened for differences in activity of the electron transport chain and glycolysis after fluvastatin treatment. We then began to expand on these results using 3D cell culture techniques to offer a more representative tumor model.

The panel of breast cancer cell lines showed a range of sensitivity to fluvastatin, with MTT50 for 72 h treatment varying from 0.7 μM for MDA-MB231 cells to 162.8 μM in BT474 cells. Interestingly, triple negative cell lines were in the sensitive range. Differences in cell cycle populations were also observed, with a representative panel of sensitive cells showing an increased G1/G0 arrest and decrease in S-phase population when compared to insensitive cell lines. Delving deeper, mitochondrial respiration was decreased in the sensitive cell lines. We also observed greater changes in morphology in the sensitive cell lines than the insensitive when grown in 3D cell culture, potentially offering more relevance to our observations.

These results confirm that there is a range of sensitivities to fluvastatin in breast cancer cell lines, allowing for further studies to determine the cause of these differences. The hints at metabolic differences could also lead to novel co-treatments with statins and greater therapeutic benefit.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C165.