Oncology
Abstract
We have developed an integrated, multidisciplinary methodology, termed systems pathology, to generate highly accurate predictive tools for complex diseases, using prostate cancer for the prototype. To predict the recurrence of prostate cancer following radical prostatectomy, defined by rising serum prostate-specific antigen (PSA), we used machine learning to develop a model based on clinicopathologic variables, histologic tumor characteristics, and cell type–specific quantification of biomarkers. The initial study was based on a cohort of 323 patients and identified that high levels of the androgen receptor, as detected by immunohistochemistry, were associated with a reduced time to PSA recurrence. The model predicted recurrence with high accuracy, as indicated by a concordance index in the validation set of 0.82, sensitivity of 96%, and specificity of 72%. We extended this approach, employing quantitative multiplex immunofluorescence, on an expanded cohort of 682 patients. The model again predicted PSA recurrence with high accuracy, concordance index being 0.77, sensitivity of 77% and specificity of 72%. The androgen receptor was selected, along with 5 clinicopathologic features (seminal vesicle invasion, biopsy Gleason score, extracapsular extension, preoperative PSA, and dominant prostatectomy Gleason grade) as well as 2 histologic features (texture of epithelial nuclei and cytoplasm in tumor only regions). This robust platform has broad applications in patient diagnosis, treatment management, and prognostication.
Authors
Carlos Cordon-Cardo, Angeliki Kotsianti, David A. Verbel, Mikhail Teverovskiy, Paola Capodieci, Stefan Hamann, Yusuf Jeffers, Mark Clayton, Faysal Elkhettabi, Faisal M. Khan, Marina Sapir, Valentina Bayer-Zubek, Yevgen Vengrenyuk, Stephen Fogarsi, Olivier Saidi, Victor E. Reuter, Howard I. Scher, Michael W. Kattan, Fernando J. Bianco Jr., Thomas M. Wheeler, Gustavo E. Ayala, Peter T. Scardino, Michael J. Donovan
Abstract
Although a causal role of genetic alterations in human cancer is well established, it is still unclear whether dietary fat can modulate cancer risk in a predisposed population. Epidemiological studies suggest that diets rich in omega-3 polyunsaturated fatty acids reduce cancer incidence. To determine the influence of fatty acids on prostate cancer risk in animals with a defined genetic lesion, we used prostate-specific Pten-knockout mice, an immune-competent, orthotopic prostate cancer model, and diets with defined polyunsaturated fatty acid levels. We found that omega-3 fatty acids reduced prostate tumor growth, slowed histopathological progression, and increased survival, whereas omega-6 fatty acids had opposite effects. Introducing an omega-3 desaturase, which converts omega-6 to omega-3 fatty acids, into the Pten-knockout mice reduced tumor growth similarly to the omega-3 diet. Tumors from mice on the omega-3 diet had lower proportions of phosphorylated Bad and higher apoptotic indexes compared with those from mice on omega-6 diet. Knockdown of Bad eliminated omega-3–induced cell death, and introduction of exogenous Bad restored the sensitivity to omega-3 fatty acids. Our data suggest that modulation of prostate cancer development by polyunsaturated fatty acids is mediated in part through Bad-dependent apoptosis. This study highlights the importance of gene-diet interactions in prostate cancer.
Authors
Isabelle M. Berquin, Younong Min, Ruping Wu, Jiansheng Wu, Donna Perry, J. Mark Cline, Mike J. Thomas, Todd Thornburg, George Kulik, Adrienne Smith, Iris J. Edwards, Ralph D’Agostino Jr., Hao Zhang, Hong Wu, Jing X. Kang, Yong Q. Chen
Abstract
Retinoic acid receptors (RARs) are members of the nuclear hormone receptor family and regulate the proliferation and differentiation of multiple different cell types, including promyelocytic leukemia cells. Here we describe a biochemical/functional interaction between the Ca2+/calmodulin–dependent protein kinases (CaMKs) and RARs that modulates the differentiation of myeloid leukemia cells. We observe that CaMKIIγ is the CaMK that is predominantly expressed in myeloid cells. CaMKII inhibits RAR transcriptional activity, and this enzyme directly interacts with RAR through a CaMKII LxxLL binding motif. CaMKIIγ phosphorylates RARα both in vitro and in vivo, and this phosphorylation inhibits RARα activity by enhancing its interaction with transcriptional corepressors. In myeloid cell lines, CaMKIIγ localizes to RAR target sites within myeloid gene promoters but dissociates from the promoter upon retinoic acid–induced myeloid cell differentiation. KN62, a pharmacological inhibitor of the CaMKs, enhances the terminal differentiation of myeloid leukemia cell lines, and this is associated with a reduction in activated (autophosphorylated) CaMKII in the terminally differentiating cells. These observations reveal a significant cross-talk between Ca2+ and retinoic acid signaling pathways that regulates the differentiation of myeloid leukemia cells, and they suggest that CaMKIIγ may provide a new therapeutic target for the treatment of certain human myeloid leukemias.
Authors
Jutong Si, LeMoyne Mueller, Steven J. Collins
Abstract
Breast cancers lacking estrogen and progesterone receptor expression and Her2 amplification exhibit distinct gene expression profiles and clinical features, and they comprise the majority of BRCA1-associated tumors. Here we demonstrated that the p53 family member p63 controls a pathway for p73-dependent cisplatin sensitivity specific to these “triple-negative” tumors. In vivo, ΔNp63 and TAp73 isoforms were coexpressed exclusively within a subset of triple-negative primary breast cancers that commonly exhibited mutational inactivation of p53. The ΔNp63α isoform promoted survival of breast cancer cells by binding TAp73 and thereby inhibiting its proapoptotic activity. Consequently, inhibition of p63 by RNA interference led to TAp73-dependent induction of proapoptotic Bcl-2 family members and apoptosis. Breast cancer cells expressing ΔNp63α and TAp73 exhibited cisplatin sensitivity that was uniquely dependent on TAp73. Thus, in response to treatment with cisplatin, but not other chemotherapeutic agents, TAp73 underwent c-Abl–dependent phosphorylation, which promoted dissociation of the ΔNp63α/TAp73 protein complex, TAp73-dependent transcription of proapoptotic Bcl-2 family members, and apoptosis. These findings define p63 as a survival factor in a subset of breast cancers; furthermore, they provide what we believe to be a novel mechanism for cisplatin sensitivity in these triple-negative cancers, and they suggest that such cancers may share the cisplatin sensitivity of BRCA1-associated tumors.
Authors
Chee-Onn Leong, Nick Vidnovic, Maurice Phillip DeYoung, Dennis Sgroi, Leif W. Ellisen
Abstract
The Fanconi anemia (FA) pathway maintains genomic stability in replicating cells. Some sporadic breast, ovarian, pancreatic, and hematological tumors are deficient in FA pathway function, resulting in sensitivity to DNA-damaging agents. FA pathway dysfunction in these tumors may result in hyperdependence on alternative DNA repair pathways that could be targeted as a treatment strategy. We used a high-throughput siRNA screening approach that identified ataxia telangiectasia mutated (ATM) as a critical kinase for FA pathway–deficient human fibroblasts. Human fibroblasts and murine embryonic fibroblasts deficient for the FA pathway were observed to have constitutive ATM activation and Fancg–/–Atm–/– mice were found to be nonviable. Abrogation of ATM function in FA pathway–deficient cells resulted in DNA breakage, cell cycle arrest, and apoptotic cell death. Moreover, Fanconi anemia complementation group G– (FANCG-) and FANCC-deficient pancreatic tumor lines were more sensitive to the ATM inhibitor KU-55933 than isogenic corrected lines. These data suggest that ATM and FA genes function in parallel and compensatory roles to maintain genomic integrity and cell viability. Pharmaceutical inhibition of ATM may have a role in the treatment of FA pathway–deficient human cancers.
Authors
Richard D. Kennedy, Clark C. Chen, Patricia Stuckert, Elyse M. Archila, Michelle A. De la Vega, Lisa A. Moreau, Akiko Shimamura, Alan D. D’Andrea
Abstract
The tumor suppressor p53 is a potent inducer of tumor cell death, and strategies exist to exploit p53 for therapeutic gain. However, because about half of human cancers contain mutant p53, application of these strategies is restricted. p53 family members, in particular p73, are in many ways functional paralogs of p53, but are rarely mutated in cancer. Methods for specific activation of p73, however, remain to be elucidated. We describe here a minimal p53-derived apoptotic peptide that induced death in multiple cell types regardless of p53 status. While unable to activate gene expression directly, this peptide retained the capacity to bind iASPP — a common negative regulator of p53 family members. Concordantly, in p53-null cells, this peptide derepressed p73, causing p73-mediated gene activation and death. Moreover, systemic nanoparticle delivery of a transgene expressing this peptide caused tumor regression in vivo via p73. This study therefore heralds what we believe to be the first strategy to directly and selectively activate p73 therapeutically and may lead to the development of broadly applicable agents for the treatment of malignant disease.
Authors
Helen S. Bell, Christine Dufes, Jim O’Prey, Diane Crighton, Daniele Bergamaschi, Xin Lu, Andreas G. Schätzlein, Karen H. Vousden, Kevin M. Ryan
Abstract
A significant challenge to efforts aimed at inducing effective antitumor immune responses is that CD8+ T cells, which play a prominent role in these responses, may be unable to respond to tumors that lack costimulatory signals and that are protected by an immune suppressive environment such as that mediated by TGF-β produced by tumor cells themselves or by infiltrating Tregs, often resulting in tolerance or anergy of tumor-specific T cells. Here we show that the in vitro activation of Cblb–/– CD8+ T cells does not depend on CD28 costimulation and is resistant to TGF-β suppression. In vivo studies further demonstrated that Cblb–/– mice, but not WT controls, efficiently rejected inoculated E.G7 and EL4 lymphomas that did not express B7 ligands and that introduction of the Cblb–/– mutation into tumor-prone ataxia telangiectasia mutated–deficient mice markedly reduced the incidence of spontaneous thymic lymphomas. Immunohistological study showed that E.G7 tumors from Cblb–/– mice contained massively infiltrating CD8+ T cells. Adoptive transfer of purified Cblb–/– CD8+ T cells into E.G7 tumor-bearing mice led to efficient eradication of established tumors. Thus, our data indicate that ablation of Cbl-b can be an efficient strategy for eliciting immune responses against both inoculated and spontaneous tumors.
Authors
Jeffrey Y. Chiang, Ihn Kyung Jang, Richard Hodes, Hua Gu
Abstract
Because of their low asparagine synthetase (ASNS) expression and asparagine biosynthesis, acute lymphoblastic leukemia (ALL) cells are exquisitely sensitive to asparagine depletion. Consequently, asparaginase is a major component of ALL therapy, but the mechanisms regulating the susceptibility of leukemic cells to this agent are unclear. In 288 children with ALL, cellular ASNS expression was more likely to be high in T-lineage ALL and low in B-lineage ALL with TEL-AML1 or hyperdiploidy. However, ASNS expression levels in bone marrow–derived mesenchymal cells (MSCs), which form the microenvironment where leukemic cells grow, were on average 20 times higher than those in ALL cells. MSCs protected ALL cells from asparaginase cytotoxicity in coculture experiments. This protective effect correlated with levels of ASNS expression: downregulation by RNA interference decreased the capacity of MSCs to protect ALL cells from asparaginase, whereas enforced ASNS expression conferred enhanced protection. Asparagine secretion by MSCs was directly related to their ASNS expression levels, suggesting a mechanism — increased concentrations of asparagine in the leukemic cell microenvironment — for the protective effects we observed. These results provide what we believe to be a new basis for understanding asparaginase resistance in ALL and indicate that MSC niches in the bone marrow can form a safe haven for leukemic cells.
Authors
Shotaro Iwamoto, Keichiro Mihara, James R. Downing, Ching-Hon Pui, Dario Campana
Abstract
Kaposi’s sarcoma herpesvirus (KSHV) is the etiologic agent for primary effusion lymphoma (PEL), a non–Hodgkin type lymphoma manifesting as an effusion malignancy in the affected individual. Although KSHV has been recognized as a tumor virus for over a decade, the pathways for its tumorigenic conversion are incompletely understood, which has greatly hampered the development of efficient therapies for KSHV-induced malignancies like PEL and Kaposi’s sarcoma. There are no current therapies effective against the aggressive, KSHV-induced PEL. Here we demonstrate that activation of the p53 pathway using murine double minute 2 (MDM2) inhibitor Nutlin-3a conveyed specific and highly potent activation of PEL cell killing. Our results demonstrated that the KSHV latency-associated nuclear antigen (LANA) bound to both p53 and MDM2 and that the MDM2 inhibitor Nutlin-3a disrupted the p53-MDM2-LANA complex and selectively induced massive apoptosis in PEL cells. Together with our results indicating that KSHV-infection activated DNA damage signaling, these findings contribute to the specificity of the cytotoxic effects of Nutlin-3a in KSHV-infected cells. Moreover, we showed that Nutlin-3a had striking antitumor activity in vivo in a mouse xenograft model. Our results therefore present new options for exploiting reactivation of p53 as what we believe to be a novel and highly selective treatment modality for this virally induced lymphoma.
Authors
Grzegorz Sarek, Sari Kurki, Juulia Enbäck, Guergana Iotzova, Juergen Haas, Pirjo Laakkonen, Marikki Laiho, Päivi M. Ojala
Abstract
Peripheral T cell lymphoma, unspecified (PTCL/U), the most common form of PTCL, displays heterogeneous morphology and phenotype, poor response to treatment, and poor prognosis. We demonstrate that PTCL/U shows a gene expression profile clearly distinct from that of normal T cells. Comparison with the profiles of purified T cell subpopulations (CD4+, CD8+, resting [HLA-DR–], and activated [HLA-DR+]) reveals that PTCLs/U are most closely related to activated peripheral T lymphocytes, either CD4+ or CD8+. Interestingly, the global gene expression profile cannot be surrogated by routine CD4/CD8 immunohistochemistry. When compared with normal T cells, PTCLs/U display deregulation of functional programs often involved in tumorigenesis (e.g., apoptosis, proliferation, cell adhesion, and matrix remodeling). Products of deregulated genes can be detected in PTCLs/U by immunohistochemistry with an ectopic, paraphysiologic, or stromal location. PTCLs/U aberrantly express, among others, PDGFRα, a tyrosine-kinase receptor, whose deregulation is often related to a malignant phenotype. Notably, both phosphorylation of PDGFRα and sensitivity of cultured PTCL cells to imatinib (as well as to an inhibitor of histone deacetylase) were found. These results, which might be extended to other more rare PTCL categories, provide insight into tumor pathogenesis and clinical management of PTCL/U.
Authors
Pier Paolo Piccaluga, Claudio Agostinelli, Andrea Califano, Maura Rossi, Katia Basso, Simonetta Zupo, Philip Went, Ulf Klein, Pier Luigi Zinzani, Michele Baccarani, Riccardo Dalla Favera, Stefano A. Pileri
Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)