Gary Schwartz

..In conclusion, preliminary data from these phase I studies indicate that the combination of raltitrexed and 5-FU is well tolerated and has encouraging clinical activity...

..An understanding of the cell cycle is critical to understanding how best to clinically develop these agents, both as single agents and in combination with chemotherapy...

..An understanding of the cell cycle and its relationship to p53 are critical for the successful clinical development of these agents for the treatment of patients with gastrointestinal cancers...

..LY293111 has antineoplastic activity in a variety of preclinical models. The tolerability and pharmacokinetics of LY293111 administered continuously, by mouth, BID for repeat cycles of 21 days was evaluated...

..We designed a phase I clinical trial of FU in combination with UCN-01...

..We evaluated the impact of Response Evaluation Criteria in Solid Tumors (RECIST), World Health Organization (WHO) criteria and tumor shape on response assessment in patients with metastatic esophageal cancer...

..Toxicity is also significant. More beneficial and safer regimens are needed...

..0 mg/m, with manageable toxicity. This combination shows encouraging activity, and survival appears promising in the pre-treated aCRC patient population. Further clinical trials are warranted...

..This phase I, open-label, first-in-human study determined dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of PD 0332991, an oral cyclin-dependent kinase 4/6 inhibitor with potent anti-proliferative activity in vitro/vivo...

..Activity in gastric cancer xenografts and in a patient with gastric cancer on the phase I trial led to this phase II study of flavopiridol in patients with metastatic gastric cancer...

..We therefore designed a phase I clinical trial of sequential paclitaxel and flavopiridol...

..Flavopiridol alone had no effect in this tumor model. Thus, flavopiridol, when combined with docetaxel in a sequence-specific manner, may provide a completely new therapeutic approach in the treatment of gastric cancer...

..The cyclin-dependent kinase inhibitor flavopiridol increases irinotecan- and fluorouracil-induced apoptosis. We conducted a phase I trial of FOLFIRI + flavopiridol in patients with advanced solid tumors...

..Moreover, checkpoint abrogation and subsequent apoptosis induced by UCN-01 do not necessarily correlate with reproductive cell death...

..Toxicity can be predicted by baseline bilirubin. Clinical activity is encouraging and may correlate to changes in p21 and Drg1 levels in patients with wild type p53 tumors following therapy...

..In conclusion, after DNA damage by Topo I poisons, flavopiridol targets homologous recombination through a p53-dependent down-regulation of Rad51, resulting in enhancement of apoptosis...

..These results indicate that flavopiridol can potently enhance the effect of gamma-radiation both in vitro and in vivo and may provide a new means to treat patients with locally advanced gastrointestinal cancers...

..Tyrosine kinase inhibitors (TKIs) of the epidermal growth factor receptor (EGFR) have activity in solid tumors. The authors evaluated an oral EGFR TKI, erlotinib, in patients with previously treated esophageal cancer...

..To determine the maximum tolerated dose (MTD), toxicities, and suitable dose for weekly 1-h paclitaxel combined with weekly cisplatin and irinotecan to treat advanced gastrointestinal malignancies...

..We sought to determine the response rate and toxicity profile of sequential paclitaxel and bryostatin-1, a novel, selective inhibitor of protein kinase C, in patients with advanced esophageal cancer...

..Methods: AZD1152 was tested in vitro and in vivo with SN-38 and CPT-11 against HCT-116 cells. Inhibition of clonogenicity, induction of apoptosis, effects on polyploidy, and tumor growth were examined...

..Preclinical data indicate that flavopiridol enhances oxaliplatin- and fluorouracil (5FU)-induced apoptosis in a sequence-dependent manner...

..The pharmacokinetics of ultrafilterable (free, non-protein bound) platinum were also determined after cisplatin (75 mg/m(2)) treatment which followed paclitaxel (175 mg/m(2)) and BNP7787 (8.2 to 27.6 g/m(2))...

..Expression of p27 in the residual rectal cancer may therefore identify patients with disease likely to be refractory to standard therapy and for whom investigational approaches should be strongly considered...

..The clinical evaluation of Drg1 in colorectal cancer has been limited. We performed this study to evaluate the role of Drg1 in a large cohort of patients with metastatic colorectal cancer who were irinotecan naive...

..Chk1 kinase is a critical regulator of both S and G(2)-M phase cell cycle checkpoints in response to DNA damage. This study aimed to evaluate the biochemical, cellular, and antitumor effects of a novel Chk1 inhibitor, CHIR124...

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..With growth inhibition at the low nanomolar range, sorafenib, by inhibiting the mitogen-activated protein kinase pathway, may prove to be a novel therapy for patients with MPNST...

..Additionally, the current study indicates that the combination of Chk1 inhibitor and gemcitabine may be particularly effective in targeting tumors with specific DNA repair defects...

..Our results indicate that targeting KIT expression and these antiapoptotic proteins with flavopiridol represents a novel means to disrupt GIST cell dependence on KIT signaling and collectively renders these cells sensitive to apoptosis...

..This phase II study was designed to further define the efficacy and toxicity of this regimen in patients with previously treated PC...

..The extent of metastatic disease and the response to chemotherapy are the major determinants of survival. Effective systemic chemotherapy should be given high priority in the treatment of stage IV rectal cancer...

..Thus, our studies establish that safingol induces autophagy through inhibition of PKCs and PI3k by safingol directly rather than via changes in endogenous sphingolipids...

..A multicenter phase II study to determine the antitumor activity of exatecan was conducted in patients with advanced cholangiocarcinoma and gallbladder carcinoma...

..We conducted a phase I study of irinotecan and the Hsp90 inhibitor 17AAG, which can also down-regulate Chk1, in patients with solid tumors...

..Taken together, 17AAG specifically inhibits the G(2)/M checkpoint in p53-defective cells by down-regulation of two critical checkpoint kinases, Chk1 and Wee1...

..Although phase II evaluation of these combination studies will provide initial evidence of anti-tumor activity, definitive phase III studies will be needed to establish this class of agents in the care of patients with cancer...

..Further evaluation of sorafenib in these and possibly other sarcoma subtypes appears warranted, presumably in combination with cytotoxic or kinase-specific agents...

..We evaluated the efficacy and safety of the addition of bevacizumab to chemotherapy in the treatment of gastric and gastroesophageal junction (GEJ) adenocarcinoma...

..To evaluate the antitumor activity and tolerability of bevacizumab and doxorubicin in patients with metastatic soft-tissue sarcoma (STS)...

..Further, we discuss the results of recent clinical trials involving the nonspecific checkpoint kinase 1 inhibitor, UCN-01, and the challenges we face with this new therapeutic approach...

..These results support the development of a clinical trial with MDM2 antagonists for liposarcoma subtypes which overexpress MDM2 and show the promise of using this expression dataset for new drug discovery in liposarcoma...

..Based on evidence of activity in preclinical and Phase I studies, the authors undertook a study of bortezomib, a reversible proteasome inhibitor, for patients with metastatic sarcomas...

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..Our results indicate that a degree of developmental maturity can be quantitatively assigned to solid tumors, supporting the notion that transformation of a solid tumor stem cell can occur at distinct stages of maturation...

..Conversely, in the absence of Drg1, Bim was stabilized and bound more abundantly to Hsp70. These results show that Drg1 renders cancer cells more resistant to chemotherapy through enhanced proteasome-mediated Bim degradation...

..Taken together, our data suggest that Drg1 is a novel gene that plays a direct role in resistance to CPT-11. Inhibition of Drg1 may provide a new means to increase the sensitivity of colon cancer cells to CPT-11...

..Thus, we propose for the first time that Aurora B determines cellular fate after an aberrant mitosis by directly regulating the Rb tumor suppressor protein...

..Therefore, combining GSIs with chemotherapy may represent a novel approach for treating metastatic colon cancers by mitigating the development of chemoresistance...

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..Dietary flaxseed (FS) is a rich source of naturally occurring antioxidants and has been shown to reduce lung IRI in mice. However, the mechanisms underlying the protective effects of FS in IRI remain to be determined...

..Further investigation is warranted to determine the strength of the correlation between bryostatin-1 activity and PARP cleavage as a surrogate molecular marker of apoptosis...

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..Although airway stenting results in significant palliation of symptoms, data regarding improved survival after stenting for advanced thoracic cancer with central airway obstruction are lacking...

..Our results confirm LOI in several tumours expressing high levels of IGF2, which may explain the observed paraneoplastic hypoglycaemia...

..The major toxicities are myalgias, nausea, and vomiting. Although there is minimal single-agent activity, combinations with standard chemotherapy are providing very encouraging results and indicate a new direction in cancer therapy...

..To further define the optimal vaccination strategy, we conducted a pilot clinical trial comparing i.m. injection with particle-mediated epidermal delivery (PMED)...

..The authors report on advanced refractory melanoma patients treated in a compassionate use trial of ipilimumab at the Memorial Sloan-Kettering Cancer Center...

..The results of our pilot study do not suggest that phase I trials always cost payers more than standard treatment...

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..conduct "proof of principle" biological assays to measure the degree of ceramide production and/or S1P inhibition, either of which may be predictive of clinical outcome or toxicity. ..

..Continue to examine the mechanisms by which flavopiridol potentiates CPT-11 induced apoptosis, which should provide the opportunity to identify new biomarkers of response for these flavopiridol drug combinations. ..

..Conduct cancer therapeutic research in a team setting in which basic and clinical scientists collaborate and interact to expedite the translation of basic research into patient-oriented therapeutic cancer research. ..

..Combining new generation drugs that specifically inhibit pathways that promote sarcoma tumor growth (mTOR and IGF- 1R/PI3K/Akt) should result in major advances in the treatment and cure of this disease. ..

..Combining new generation drugs that specifically inhibit pathways that promote sarcoma tumor growth (mTOR and IGF- 1R/PI3K/Akt) should result in major advances in the treatment and cure of this disease. ..

..This K24 award mechanism represents the essence of what we are proposing and for which support is needed. ..

..g increase in cdk2 activity); 3) To determine whether a specific PKC isofrom may be a critical target for drug development in induction of apoptosis with chemotherapy by testing PKC antisense for specific isoforms in a laboratory model. ..

..The long-term goal of this phase I study will be to increase the therapeutic benefit of CPT-11 and to identify those patients who would most benefit from the drug combination. ..

..Dose reductions are allowed in the setting of toxicity. Imaging studies will be performed on an every 6 week schedule. ..