Branimir I. Sikic - US grants

Cyano-morpholino-adriamycin (MRA-CN) and some of its congeners represent a new and exciting sub-class of anticancer drugs. They exhibit major differences in pharmacodynamic properties and in their apparent mechanisms of action from other anthracyclines. The antitumor activity of MRA-CN is markedly more potent (500 to 1000-fold) than doxorubicin (DOX), both in cell lines and in transplantable tumor models, with no corresponding increase in cardiac toxicity. MRA-CN produces cross-linking of DNA, unlike other anthracyclines. MRA-CN is not cross resistant with DOX or other anthracyclines in DOX-selected variants of P388 leukemia and the human sarcoma cell line, MES-SA. The purpose of this proposal is to study the cellular pharmacology of MRA-CN, with regard to its selectivity, mechanisms of action and resistance, and modulation by other agents. Preliminary data indicate that the major normal tissue toxicity of MRA-CN may be to the bone marrow. We will be able to study the drug sensitivities of bone marrow CFU-C from patients with lymphomas and leukemias in remission, as well as in cell lines derived from their tumors before and after treatments. A therapeutic index will then be estimated in vitro for MRA-CN and compared directly to DOX and melphalan as model anthracyclines and alkylating agents. It is likely that some of the paired cell lines will differ in their MRA-CN sensitivity after patients have relapsed from anthracycline and alkylator containing regimens, or that some lines will be resistant to MRA-CN (relative to marrow) a priori. These lines which are resistant de novo or after treatments in vivo will be used for further studies of possible mechanisms of resistance, cross-resistance and selective modulation. The ability to obtain and propagate both tumor cell lines and normal marrow from the same patient offers an ideal opportunity for reproducible in vitro observations on clinically derived material. In addition, resistance to MRA-CN will be developed by step-wise exposure to MRA-CN in vitro. DOX and MRA-CN cellular accumulation, DNA cross-link formation and repair, and glutathione pathways will be assessed in the paired sensitive and resistant lines. Possible sensitizing effects of modulators of pleiotropic resistance (e.g., verapamil and tamoxifen), inhibitors of glutathione synthesis (buthionine sulfoximine), and agents which interact with alkylators (misonidazole) will be assessed. The selectivity of any such modulation relative to human bone marrow will be evaluated. Finally, the extreme potency and non-basicity of the amino-nitrogen of MRA-CN make it an attractive candidate for liposomal encapsulation and monoclonal antibody-liposome targeting, offering the potential for greatly increased selectivity.

The purpose of this proposal is to study the clinical significance of multidrug resistance in breast and ovarian carcinomas, lymphomas, and Hodgkin's disease. These tumors were chosen because: (1) they are moderately curable in patients with minimal disease (breast and ovarian cancers) and in advanced stages (lymphomas and Hodgkin's disease); and (2) we have shown significantly increased mdr1 gene expression in patients with these cancers who have failed chemotherapy, suggesting that this mechanism may be responsible for the resistance and that its reversal may result in clinical remission of tumors. A series of Phase I and II clinical trials are proposed to modulate mdr1 expression in these cancers. Important features of these trials are: (1) Serial sampling of tumors by fine needle aspiration, with assessment of mdr1 expression by both immunocytochemistry for P-glycoprotein and RNA- directed polymerase chain reaction (PCR). (2) Detailed pharmacokinetic studies to determine the effects of the modulating agent upon the disposition and effective dose exposure (plasma area under the curve) of the cytotoxic drug. (3) Patients will serve as their own controls with pharmacokinetic studies both with and without the modulating drug. (4) Monitoring of the level of the modulating agent in all patients to determine whether adequate levels of free drug have been achieved. (5) The combination of etoposide and cyclosporine will be used in the first set of protocols. If cyclosporine plus etoposide produce remissions in at least 20% of refractory patients, a second generation of studies will add doxorubicin and vinblastine to this combination. If cyclosporine is unsuccessful we will study cefoperazone, an antibiotic which we have shown to be an effective modulator in preclinical experiments. The second aspect of the proposal concerns retrospective studies of mdr1 expression in these tumors, for which extensive data bases of clinical characteristics and outcome and other pathological correlations are available at Stanford. Expression of mdr1 will be determined in stored frozen tissues by immunochemistry and PCR, and in paraffin-embedded fixed tissues by immunochemistry. Results will be analyzed by multivariate analysis in comparison to other known and potential factors for prognostic importance in tumor response to chemotherapy and patient survival. This proposal represents an integrated effort by a team of medical oncologists and pathologists at Stanford University School of Medicine to further understand and reverse the function of the multidrug resistance gene in these cancers, with the long-term goal of increasing their curability.

PSC 833 (valspadar) is a non-immunosuppressive and non-nephrotoxic cyclosporin analogue which is a potent inhibitor of the multidrug resistance transporter, P-glycoprotein. P-glycoprotein is expressed in 70 to 80% of colon cancers and may be an important mechanism of resistance to paclitaxel. The goal of this study is to assess the remission rate of the combination of paclitaxel and PSC 833 in this type of cancer. Seven patients have been enrolled to date, with a target of between 19 and 30 patients total over the next two years. No data are yet available.

PSC 833 (valspadar) is a non-immunosuppressive and non-nephrotoxic cyclosporin analogue which is a potent inhibitor of the multidrug resistance transporter, P-glycoprotein. Protocol #432 is of interest because of the activity of paclitaxel and doxorubicin in breast, ovarian and lung cancers. In this Phase I study, we are assessing the effect of PSC 833 on the pharmacokinetics and pharmacodynamics of doxorubicin and paclitaxel, with the goal of defining: a) a maximally tolerated dose (MTD) of doxorubicin with paclitaxel, and PSC, utilizing G-CSF support. Patients initially receive doxorubicin and paclitaxel and are being enrolled in cohorts of three to ten patients per cohort. Detailed phamacokinetics for doxorubicin, doxorubicinor, and paclitaxel are being performed. We anticipate that PSC 833 will significantly increase the area under the curve and the half-life of both doxorubicin and paclitaxel. This study is ongoing and should be completed during the current grant year.

This is a study of the optimal dose, toxicities, and kinetics of an antisense oligonucleotide targeted against protein kinase C alpha, a signaling protein thought to be important in the growth regulation of some cancers. Cohorts of three patients each are being entered into the study beginning at a dose of 0.5 mg/kg/day for 21 day infusions. Twelve patients have been entered into the study thus far in the first four cohorts. The treatments have been well tolerated, including in one patient who has received a total of six months of therapy and has evidence of regression of tumor. We plan to complete the study in the coming year, and to follow it.

This is a Phase II study of an antisense olionucleotide, ISIS 3521, in ovarian carcinoma. The study is based on the dose determined from our Phase I study, Protocol # 482, 2 mg/kg/day for 21 days. 12 patients have been enrolled and no results are yet available.

This was a study of the optimal dose, toxicities, and kinetics of an antisense oligonucleotide targed against protein kinase C alpha, a signaling protein thought to be important in the growth regulation of some cancers. Cohorts of three patients each were entered in to the study beginning at a dose of 0.5mg/kg/day for 21 day infusions. Twenty one patients have entered into this study in 5 cohorts of patients. Dose limiting toxicity was observed at the highest dose of 3.0 mg/kg/day, and consisted of severe fatigue as well as thrombocytopenia with clinically significant bleeding. The maximum tolerated dose was defined as 2.0 mg/kg/day over 21 days. Evidence of tumor response was observed in three of four patients with ovarian cancer. Steady state plasma levels of the antisense compound were achieved by 24 hours and were proportional to the dose administered. This study served as a foundation for three subsequent protocols including a Phase II study of antisense oligonucleotide alone in ovarian cancer, a Phase I stydy of a weekly infusion schedule, and a Phase I study of antisense with chemotherapy.

This is a Phase I study of the optimal dose, toxicities, and kinetics of an antisense oligonucleotide targeted against protein kinase C alpha when administered with chemotherapy consisting of carboplatin and paclitaxel. It is based on our prior Phase I trial, Protocol #482. Cohorts of 3 to 6 patients each are being entered into the study beginning at an antisense dose of 1.0 mg/kg/day over 14 days by continuous infusion. Carboplatin and paclitaxel are administered on day 4 of the antisense infusion. The doses of antisense oligonucleotide and carboplatin will be escalated sequentially in successive cohorts if the prior doses are well tolerated. We are presently enrolling patients in the final cohort of the Phase I Study. We plan to extend this study to an additional sixteen patients with non-small cell lung cancer at the final cohort's doses to evaluate these patients for responses. Six out of eight patients with non-small cell lung cancer had patial responses in our phase I study. Four patients have entered the trial in the first cohort. The main side effects seen thus far include diarrhea, nausea and vomiting, which are primarily due to the chemotherapy but may be exacerbated by the antisense drug. We plan to complete the study in the coming year.

human therapy evaluation; combination cancer therapy; neoplasm /cancer chemotherapy; colorectal neoplasms; paclitaxel; cyclosporines; outcomes research; multidrug resistance; carcinoma; neoplasm /cancer remission /regression; metastasis; P glycoprotein; clinical research; human subject;

Overexpression of PKC, a cytoplasmic serine/threonine kinase involved in signal transduction, may promote the development and maintenance of tumors. We have previously reported safety and activity of ISIS 3521 at 2.0 mg/kg by a 21 day CI. The present study explored an alternate schedule of 24 hr CI once weekly. Between 1/98-11/98, 11 patients with refractory solid tumors received ISIS 3521 at doses of 6, 12, 18 and 24 mg/kg in cohorts of 3 to six. 91 doses have been delivered so far. No gr 4 toxicities occurred. Gr 3 toxicities were: fever/chills (n =1) and hemorrhage (n =1) at 18 mg/kg and chills (n =1) at 24 mg/kg. Other gr 1/2 toxicities include thrombocytopenia (4), myalgias (6), chills (7), headache (3), fatigue (4), fever (7) and nausea/vomiting (4) which were transient. Steady state plasma levels were achieved within 4 hr and were proportional to increasing dose. Primate studies had identified complement activation as a potential toxicity of ISIS 3521; therefore, split products (C3a and Bb) were analyzed in all patients. Transient activation was seen at doses > 18 mg/kg when compared to < 18 mg/kg (median 3.9 versus 1.4- fold increase in C3a, p<0.001 and median 1.9 versus 1.0- fold increase in Bb, p<0.001). This correlated with a 1.5 second prolongation of prothrombin time (p<0.001) but not with grade 1-2 thrombocytopenia. Clinical evidence of complement activation was not observed. One patient had stable colon cancer for 3+ months. This regimen appears acceptable and patient accrual is currently ongoing to determine the MTD.

The purpose of this proposal is to conduct clinical trials of modulation of resistance to cytotoxic drugs. Studies of new modulators of MDR1/P-glycoprotein (P-gp) multidrug resistance (MDR) will continue. Additional areas of focus include: (1) modulation of other MDR mechanisms (the MDR-associated protein MRP, and the bcl-2 family of inhibitors of apoptosis); and (2) the use of P-gp inhibitors to enhance the oral bioavailability of taxanes and other P-gp substrate drugs. Aim 1: To conduct Phase I trials of modulation of multidrug resistance mechanisms. We will conduct 1-2 Phase I trials per year, defining toxicities, optimal doses and schedules, and drug disposition. Planned studies include: PSC 833 (PSC)/Doxil/paclitaxel; LY335979/mitoxantrone; LY335979/doxorubicin/paclitaxel; and other, new MDR1 modulators. Similar approaches will be applied to a new inhibitor of MRP, with doxorubicin and with etoposide; and antisense oligonucleotide drugs against bcl-2 and bcl-xl. We will choose these new agents based on animal toxicology, other preclinical data, and availability for clinical trials. An eventual goal is combined blockade of two mechanisms (e.g., MDR1 and MRP). Aim 2: To study pharmacokinetic interactions associated with modulation of drug resistance. An important issue with modulators of drug resistance is the effect of these drugs on normal tissue function and in particular on the disposition of cytotoxins. Pharmacokinetic studies will involve compartmental methods to further define drug interactions, and validation of optimal sampling strategies with Bayesian estimations. The effect of different modulators (PSC vs. LY335979) on the erythromycin breath test in patients will be used to dissect the role of cytochrome P450 3A4 in these interactions. Ancillary pharmacokinetic studies of mitoxantrone and etoposide for the ECOG and POG trials of MDR1 modulation in acute myeloid leukemias will also be supported. Aim 3: To enhance the oral bioavailability of MDR1-related drugs by co-administration with inhibitors of P-gp. Intestinal P-gp is a major barrier to the absorption of taxanes and other MDR1 related cytotoxins. We will co-administer modulators and cytotoxins in trials designed to enhance bioavailability, and potentially to increase the safety and convenience of chemotherapy. Patients will receive an initial course of the cytotoxin intravenously, followed by sequential courses of the cytotoxin orally together with increasing doses of the P-gp inhibitor. The first protocol in this aim will involve paclitaxel with PSC. Other cytotoxins of interest for this approach include taxotere, etoposide, and vinorelbine.

Valspodar (PSC 833) is a potent inhibitor of the multidrug resistance transporter P-glycoprotein. This drug is being evaluated along with Doxil and Paclitaxel (both of which are MDR substrates) in refractory solid tumors to determine the maximum tolerated dose of the drug alone and in combination with PSC.

human therapy evaluation; quinoline; prostate neoplasms; drug screening /evaluation; mitoxantrone; neoplasm /cancer chemotherapy; clinical trial phase I; inhibitor /antagonist; combination chemotherapy; multidrug resistance; P glycoprotein; clinical research; human subject; male;

The intestines have a high expression of P-glycoprotein (a drug efflux pump) which may be responsible for lack of absorption of certain chemotherapy drugs which are MDR substrates, i.e. Paclitaxel. In the study Paclitaxel is administered orally along with the MDR inhibitor Valspodar with the goal of determining the maximum tolerated dose.

DESCRIPTION: (Applicant's Description) Cancers of unknown primary site are a diagnostic and therapeutic dilemma in oncology. Information from DNA micro array technologies on the gene expression profile of cancers has led to the hypothesis that there are diagnostic sets of genes which can resolve the origin of unknown primary cancers (UPC) with a high degree of confidence. The purpose of this project is to test this hypothesis, by both retrospective and prospective analysis of cases of UPC from Stanford Medical Center and the Sarah Cannon Cancer Center, in the context of a rapidly evolving database of site-specific clusters of gene expression. Specific Aims are: (1) Definition of the gene expression profile of known human cancers. We now have extensive information on the profiles of lymphomas, leukemia, and carcinomas of the breast, prostate, lung, ovary, and liver. Additional tumors to be accrued from our tumor bank and ongoing sample acquisitions include sarcomas, germ cell cancers, melanomas, mesotheliomas, and carcinomas of the colon, stomach, pancreas, bladder, and kidney. (2) Determination of the diagnostic cluster of gene expression for each of the above tumor types. We anticipate that several hundred genes may differentiate one from the others of these known tumors. (3) Acquisition, gene expression profiling, and diagnostic classification of unknown primary cancer specimens. This aim will involve a close collaboration with the world's leading center for the clinical evaluation of unknown primary cancers, the Sarah Cannon Cancer Center in Nashville. (4) Evaluation of a panel of histospecific antisera for diagnostic utility with UPC specimens. This aim will utilize retrospective archived specimens as well as prospectively acquired samples from this project. (5) Identification of specific or clustered gene expression associated with known prognostic factors, response to therapies, and survival of patients with UPC.

DESCRIPTION (PROVIDED BY APPLICANT): MDR1 gene expression is an important prognostic marker in many human cancers. This application focuses on the underlying mechanisms responsible for regulating the expression of MDR1, particularly involving the NF-IL6 family of transcriptional regulators. Aim 1. To Study the Role of NF-IL6 in Activating or Suppressing MDR1 Expression. The hypothesis is that altered expression of NF-IL6 family members in human cancer cells may be responsible for MDR1 activation in these cells. Experimental approaches will include co-transfection of MDR1 promoter constructs and different forms of NF-IL6, quantitative analysis of NF-IL6 family members in nuclear and cytoplasmic extracts, and studies of the phosphorylation status of NF-IL6 species in cellular models. Aim 2. To Study Protein-Protein Interactions Mediated by NF-IL6 in MDR1. An NF-IL6-2 interacting site was mapped in MCF-7 cells within -128 to -75 of the MDR1 P1 promoter, a region which lacks NF-IL6 binding motifs. NF-IL6 may activate the MDR1 promoter through multiple interaction sites. Physical interactions among NF-IL6 family members, the Y-box-associated factors (NF-Y and YB-1), and AP1 (c-fos and c-jun) will be verified in vitro by GST pull down experiments utilizing a GST-NF-IL6 fusion protein to precipitate factors in nuclear extracts of MDR cell lines. Once protein interactions are established, their functional role in regulating the chromosomal MDR1 gene will be examined in stable transfectants containing MDR1 constructs. Aim 3. To Investigate a Novel Activator Involved in MDR1 Regulation. The hypothesis is that that there is a novel binding protein, other than NF-IL6, responsible for maintaining basal promoter activity in MCF-7 cells. The plan is to identify the protein and its gene binding to the -148 to -140 element by mobility shift assays as well as the yeast one-hybrid system. Sense and antisense cDNAs for this binding protein will be transfected into both MCF-7 and MCF-7/ADR cells to test their capacity to activate or modulate MDR1 expression. Aim 4. To Study MDR1 Regulation in Clinical Specimens. The focus will be on acute myeloid leukemia (AML) as a clinical model for MDR1 expression. MDR1 will be analyzed by rtPCR and flow cytometry. NF-IL6 members will be quantitatively analyzed in both nudear and cytoplasmic extracts of AML.

leucovorin; neoplasm /cancer chemotherapy; colorectal neoplasms; fluorouracil; drug screening /evaluation; antineoplastics; combination chemotherapy; kinase inhibitor; clinical trial phase I; cytotoxicity; pharmacokinetics; diarrhea; epidermal growth factor; growth factor receptors; human therapy evaluation; patient oriented research; human subject; clinical research;

gemcitabine; human therapy evaluation; oligonucleotides; combination chemotherapy; neoplasm /cancer chemotherapy; antisense nucleic acid; BCL2 gene /protein; clinical trial phase I; apoptosis; patient oriented research; human subject; clinical research;

carboplatin; diterpenes; drug screening /evaluation; combination chemotherapy; neoplasm /cancer chemotherapy; clinical trial phase I; paclitaxel; patient oriented research; clinical research; human subject;

epothilon; analog; neoplasm /cancer pharmacology; drug screening /evaluation; neoplasm /cancer chemotherapy; clinical trial phase I; drug administration rate /duration; intravenous administration; pharmacokinetics; cytotoxicity; patient oriented research; human subject; clinical research;

[unreadable] DESCRIPTION (provided by applicant): This proposal will study non-MDR1 genetic and cellular determinants of taxane therapy in breast and ovarian cancers. We have established 17 taxane-resistant variants from 4 breast and 6 ovarian cancer cell lines, and we hypothesize that these diverse variants may yield insight into novel mechanisms of resistance to taxanes. The specific aims are: 1. To determine tubulin isoform content and potential alterations in microtubule dynamic instability. Our analyses of the expression of the six classes of (3- tubulin isoforms reveal altered p-tubulin content in many of the taxane-resistant variants. Microtubule assembly in these cells will be assessed in collaboration with Dr. Mary Ann Jordan. 2. To study the effects of altered tubulin and microtubule associated protein genes on drug sensitivity. Several of the variants have down-regulated MAP4 and up-regulated MAP Tau, and we hypothesize that these alterations may have an adverse effect on taxane sensitivity by altering taxane binding. We plan to use siRNA technology to study the effects of these genes and specific tubulin isoforms, and inducible vectors utilizing tetracycline regulation will be used to transfect genes of interest into parental cells. 3. To explore regulators of apoptosis (e.g. Bcl-2, Bcl-XL, Akt) and cell growth (e.g. EGFR-1, her2) as determinants of response to taxanes. Several of the non-P-gp variants possess altered expression of apoptotic regulators. We will use antisense and RNAi approaches to study the effects of inhibition of these regulators on cellular sensitivity to taxanes. We will also determine the effects of inhibition of growth pathways on taxane sensitivity by inhibiting EGFR-1, her2, Akt and other genes using kinase inhibitors. 4. To identify novel genetic markers to predict resistance to taxanes. Genetic (array CGH) and genomic (microarray gene expression profiling) approaches will be used to search for novel genetic markers for the prediction of sensitivity and resistance to taxane therapy. Candidate genes will be validated by PCR, immunoblotting, and tet-regulated expression using an MCF-7 Flp-ln line which we have made. 5. To study taxane resistance in clinical specimens of breast and ovarian cancer. Whole genome profiling of tumor specimens from breast and ovarian cancers from the NCI Cooperative Human Tissue Network, annotated for responsiveness to taxane therapy, will be performed. Expression of resistance factors identified in cellular models will also be validated in these specimens. In summary, this project will use a large set of unique models of cellular resistance to taxanes in ovarian and breast cancer cell lines and clinical specimens obtained from patients treated with taxanes to: (1) study the relevance of known resistance mechanisms to these drugs, (2) explore new mechanisms, and (3) develop clinical markers for response. [unreadable] [unreadable] [unreadable] [unreadable]

Overview Goal and Objectives The goal of this resource is to support an increasing number of high quality, innovative, investigator-initiated early-phase clinical trials by providing experienced research nursing and data management support exclusively for the management of these trials. The availability of this research support is essential for trials that have high levels of complexity, high demand for specimens, and/or increased need for patient surveillance and interactions. Patients entered onto these predominantly Phase I or Phase I/II trials will have increased need for specialized research nursing to insure that 1) all consent is particularly well informed; 2) all adverse events are detected; 3) all requisite samples are obtained at the appropriate time and with expeditious and careful processing; and 4) feedback to and from the patients is maintained at an optimal level. Investigators making use of this facility will have the availability of the Cancer Center Shared Resources for tissue and genetic analyses, enabling clinical investigators without their own laboratories to initiate investigator-initiated protocols that include correlative studies. Rationale Stanford's Developmental Therapeutics group and their activities within the Molecular Therapeutics Program have been expanding. The vision over the next five years is to make early-phase clinical/translational research built on Stanford science the highest priority of the Cancer Center. The Freidenrich Center for Translational Research, to be completed in 2012, will be dedicated to this mission and will provide integrated space for patient treatment, research nursing support, and data management in a single location. This physical proximity, together with Dr. Sikic's (Associate Director Clinical Research; 05: Therapeutics) leadership and recent, anticipated recruitments in the areas of translational medicine and Phase I/II trial capability, will provide an ideal environment for the expansion of the early phase cancer clinical trial program.

DESCRIPTION (provided by applicant): Serous ovarian cancers (SOCs) are unusual among epithelial cancers in that some (10-15%) are curable by chemotherapy in stages 3 and 4. SOCs are complex entities in which a pathologically symbiotic interplay occurs between cancer cells and immune, inflammatory, vascular and stromal cells. We propose to study proteomic profiles of SOCs at the single-cell level in many malignant and normal cell types, including tumor-initiating cell populations that can re-establish a complete tumor cell hierarchy post treatment. Multi-dimensional (>40 parameters per cell) mass cytometry affords unprecedented opportunities to measure these responses simultaneously in the multiple cell types that comprise the tumor and, in so doing, to identify pathways and mechanisms associated with ex vivo drug sensitivity and resistance. Thus, we will assess both basal and drug-evoked proteomic signatures for carboplatin (PT), paclitaxel (TX) and selective pathway inhibitors. A major challenge in SOC is to enhance cure by initial PT and TX. Our goals are to identify predictive therapeutic biomarkers for PT, TX, and novel combinations with PT/TX. The aims are: (1) Utilize mass cytometry to identify proteomic profiles that designate the relative responsiveness of SOC drug-sensitive and resistant cell models to PT, TX, and two potential sensitizing pathways: IAPs and CCL2/CCR2. This aim will utilize 12 drug-resistant cell models derived from 6 parental lines. In our preliminary data, IAP and CCL2 inhibition enhances the efficacy of PT and TX. Combinations of inhibitors will be evaluated with PT and TX for their ability to promote cell death in the cell models and tumor regression in xenografts. (2) Validate these proteomic profiles and therapeutic targets in SOC clinical specimens. We have an existing viably frozen SOC tumor bank of more than 50 specimens and plan to study a total of 90 during this project. Xenografts from selected clinical specimens will be utilized to assess drug responsiveness in vivo, with harvesting of tumors for mass cytometric assays. (3) Perform genomic studies using mutation analyses and expression profiles of the SOC cell models and clinical specimens. These will be analyzed in conjunction with the TCGA and Tothill databases, applying novel computational tools for combining mass cytometry analysis with transcriptomic, epigenetic and exomic databases. The genomic analyses will facility the identification of new candidate therapeutic biomarkers for mass cytometry, as well as additional therapeutic targets for PT/TX combinations. The scientific benefits of this project will be new insights into SOC curability via determinants of drug responsiveness at the functional proteomic and molecular level. The expected benefits to patients are the ability to identify responders at diagnosis, new drug combinations leading to new clinical trials, and tailoring therapies prospectively for individual patients.

DESCRIPTION (provided by applicant): As a Network Lead Participating Site, the Stanford Cancer Institute (SCI) will provide overall leadership to ensure the collaboration and success of the U10 leadership team and of individual investigators who are active in enrolling patients onto cooperative group studies as participants in the NCTN. Stanford has a long history of active participation across multiple NCTN cooperative groups as evidenced by a strong publication lists and clinical trial enrollment. With this history and with the strong support from SCI leadership, a well-functioning and centralized CCTO, strong basic science and translational medicine, and increasing support for clinical research from Stanford Hospitals and Clinics, Stanford investigators are poised to continue their leadership and markedly enhance accrual to cooperative group studies in the NCTN.