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3-AP and Gemcitabine in Treating Patients With Advanced Solid Tumors or Lymphoma

ABSTRACT: This phase I trial is studying the best dose of 3-AP and the side effects of giving 3-AP together with gemcitabine in treating patients with advanced solid tumors or lymphoma. Drugs used in chemotherapy, such as 3-AP and gemcitabine (GEM), work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. 3-AP may help gemcitabine kill more cancer cells by making the cells more sensitive to the drug. 3-AP may also stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

DISEASE(S): Extranodal Marginal Zone B-cell Lymphoma Of Mucosa-associated Lymphoid Tissue,Lymphoma, Large B-cell, Diffuse,Stage Iv Adult T-cell Leukemia/lymphoma,Stage Iv Adult Diffuse Large Cell Lymphoma,Lymphoma, Large-cell, Immunoblastic,Small Intestine Lymphoma,Stage Iv Adult Diffuse Mixed Cell Lymphoma,Stage Iv Adult Immunoblastic Large Cell Lymphoma,Recurrent Grade 1 Follicular Lymphoma,Sezary Syndrome,Splenic Marginal Zone Lymphoma,Mycosis Fungoides,Lymphoma, Mantle-cell,Stage Iv Adult Lymphoblastic Lymphoma,Stage Iii Adult Burkitt Lymphoma,Leukemia-lymphoma, Adult T-cell,Stage Iii Adult Diffuse Small Cleaved Cell Lymphoma,Recurrent Adult Immunoblastic Large Cell Lymphoma,Stage Iv Grade 1 Follicular Lymphoma,Recurrent Adult Burkitt Lymphoma,Stage Iv Mantle Cell Lymphoma,Primary Central Nervous System Non-hodgkin Lymphoma,Leukemia, T-cell,Plasmablastic Lymphoma,Stage Iv Mycosis Fungoides/sezary Syndrome,Lymphoma, B-cell, Marginal Zone,Burkitt Lymphoma,Stage Iii Mycosis Fungoides/sezary Syndrome,Recurrent Adult Diffuse Small Cleaved Cell Lymphoma,Stage Iii Grade 1 Follicular Lymphoma,Stage Iii Adult Immunoblastic Large Cell Lymphoma,Nodal Marginal Zone B-cell Lymphoma,Stage Iii Marginal Zone Lymphoma,Stage Iii Adult Diffuse Mixed Cell Lymphoma,Recurrent Small Lymphocytic Lymphoma,Lymphoma, T-cell, Cutaneous,Stage Iv Adult Burkitt Lymphoma,Recurrent Marginal Zone Lymphoma,Stage Iii Adult T-cell Leukemia/lymphoma,Waldenstrom Macroglobulinemia,Lymphoma, Follicular,Stage Iii Adult Diffuse Large Cell Lymphoma,Leukemia, Lymphocytic, Chronic, B-cell,Intraocular Lymphoma,Stage Iii Cutaneous T-cell Non-hodgkin Lymphoma,Recurrent Mantle Cell Lymphoma,Recurrent Grade 3 Follicular Lymphoma,Stage Iii Adult Hodgkin Lymphoma,Leukemia,Hodgkin Disease,Primary Central Nervous System Hodgkin Lymphoma,Recurrent Adult Hodgkin Lymphoma,Mycoses,Stage Iii Grade 2 Follicular Lymphoma,Waldenström Macroglobulinemia,Angioimmunoblastic T-cell Lymphoma,Recurrent Adult Lymphoblastic Lymphoma,Stage Iv Marginal Zone Lymphoma,Unspecified Adult Solid Tumor, Protocol Specific,Lymphoma, Large-cell, Anaplastic,Stage Iv Adult Hodgkin Lymphoma,Stage Iii Mantle Cell Lymphoma,Lymphoma, T-cell,Stage Iii Grade 3 Follicular Lymphoma,Stage Iv Grade 3 Follicular Lymphoma,Stage Iv Adult Diffuse Small Cleaved Cell Lymphoma,Immunoblastic Lymphadenopathy,Precursor Cell Lymphoblastic Leukemia-lymphoma,Recurrent Cutaneous T-cell Non-hodgkin Lymphoma,Stage Iv Small Lymphocytic Lymphoma,Lymphoma,Recurrent Mycosis Fungoides/sezary Syndrome,Anaplastic Large Cell Lymphoma,Recurrent Adult Diffuse Mixed Cell Lymphoma,Stage Iii Small Lymphocytic Lymphoma,Recurrent Grade 2 Follicular Lymphoma,Stage Iv Cutaneous T-cell Non-hodgkin Lymphoma,Stage Iv Grade 2 Follicular Lymphoma,Recurrent Adult T-cell Leukemia/lymphoma,Lymphoma, Non-hodgkin,Stage Iii Adult Lymphoblastic Lymphoma,Recurrent Adult Diffuse Large Cell Lymphoma,Lymphoma, B-cell

PROVIDER: 2026481 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Project description:Purpose: Chemotherapy is pivotal in the multimodal treatment of pancreatic cancer patients. In recent years, technical advances have developed experimental methods that unveiled a high degree of inter- and intratumoral heterogeneity in pancreatic cancer. We hypothesized that intratumoral heterogeneity (ITH) impacts response to gemcitabine treatment and demands specific targeting of resistant subclones. Experimental Design: We addressed the effect of ITH on response to gemcitabine treatment using single cell-derived cell lines (SCDCL) from the classical-like cell line BxPC3 and the basal-like cell line Panc-1 which were analyzed by mRNA-seq and mass spectrometry. Results: Individual SCDCLs of the parental tumor cell populations of BxPC3 and Panc-1 showed considerable heterogeneity in response to gemcitabine. Unsupervised principal component analysis (PCA) including the 1,000 most variably expressed genes showed a clustering of the SCDCLs according to their respective sensitivity to gemcitabine treatment for BxPC3, while this clustering was less clear for Panc-1. In BxPC3 SCDCLs, enriched signaling pathways EMT, TNF signaling via NfKB, and IL2STAT5 signaling correlated with more resistant behavior to gemcitabine. In Panc-1 SCDCLs MYC targets V1 and V2 as well as E2F targets were associated with stronger resistance to gemcitabine. Feature extraction of proteomes again identified less proteins whose expression was associated with the response of individual SCDCLs in Panc-1 compared to BxPC3. Based on molecular profiles, we could show that the gemcitabine-resistant SCDCLs of both BxPC3 and Panc-1 are more sensitive to the BET inhibitor JQ1 compared to the respective gemcitabine-sensitive SCDCLs. Conclusions: Our model system of SCDCLs identified gemcitabine-resistant subclones within a parental tumor population and provides evidence for the critical role of ITH for treatment response in pancreatic cancer. Through molecular profiling, we identified specific signaling pathways and protein signatures that might help to explain the differential response to treatment among clones. We exploited these molecular differences for an improved and more targeted therapy of resistant subclones of a heterogeneous tumor.

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3-AP and Gemcitabine in Treating Patients With Advanced Solid Tumors or Lymphoma

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