Highlights from Recent Cancer Literature

Abstract

Novitskiy SV, Pickup MW, Gorska AE, Owens P, Chytil A, Aakre M, et al. TGF-β receptor II loss promotes mammary carcinoma progression by Th17 dependent mechanisms. Cancer Discovery 2011;1:430–41.Population-based studies have revealed several subtypes of human breast cancer based on transcriptome profiling, each correlating with distinct survival outcomes and responses to standard-of-care therapy. Whereas patients with estrogen receptor (ER)-positive breast cancer benefit from treatment with tamoxifen, efficacious long-term treatment for lymph node-positive, ER-negative (e.g., luminal B) breast cancer is currently lacking. Using a mouse model of luminal B-type mammary carcinogenesis (i.e., MMTV-PyMT mice), Novitskiy and colleagues have revealed an important interaction between TGF-β and interleukin (IL)-17. Mammary tumors in MMTV-PyMT mice lacking TGF-β receptor-2 (TGF-βR2), like human breast carcinoma cells, exhibited enhanced sensitivity to IL-17, as evidenced by increased mammary epithelial cell expression of CXCL1 and CXCL5, chemokines involved in recruitment of myeloid-derived suppressor cells (MDSC). MDSCs (and macrophages) in TGF-βR2-deficient tumors exhibited high levels of Th17 cytokines (TGF-β, IL-6, and IL-23) correlating with 3.5-fold higher levels of Th17-CD4+ T cells. Moreover, MDSCs also expressed high levels of several immunosuppressive molecules, including arginase, IDO, and COX2. Treatment of tumor-bearing mice with an anti-IL-17 monoclonal antibody decreased primary tumor growth and pulmonary metastasis by reducing the presence of Th17 cells, mediated by reduced expression of CXCL1, and further reduced expression of arginase, matrix metalloproteinase-13, and TGFB, significant mediators of MDSC T-cell suppressive activity. Transcriptome analysis of human breast cancers revealed an IL-17 gene expression signature that included these cytokines that was correlated with worse clinical outcome for lymph node-positive, ER-negative luminal B breast cancer. Together, these data indicate that patients with luminal B-type breast cancers harboring loss-of-function mutations in the TGF-βR2 pathway may benefit from therapeutics selectively targeting the IL-17 pathway.Sugiarto S, Persson AI, Munoz EG, Waldhuber M, Lamagna C, Andor N, et al. Asymmetry-defective oligodendrocyte progenitors are glioma precursors. Cancer Cell 2011;20:328–40.The cells of origin for most cancers remain unknown. For many cancers, both stem and progenitor cells have been proposed as cells of origin, with progenitor-derived cancers generally showing improved response to therapy in comparison with stem cell-derived tumors. For brain tumors in particular, a progenitor origin has been proposed for specific subclasses of glioblastoma multiforme, a tumor of astrocytes, and for oligodendroglioma, a tumor of oligodendrocytes. Yet, it remains uncertain how brain cancers become initiated from either the stem or the progenitor cell compartment. To address this question, Sugiarto and colleagues analyzed genetically engineered mouse models and human oligodendroglioma. In these systems, normal glial progenitor cells divided asymmetrically, with one daughter becoming a progenitor (marked by retention of the progenitor marker NG2) and the second daughter (with decreased NG2) differentiating to become an oligodendrocyte. The authors went on to demonstrate that asymmetric segregation of NG2 promoted similar asymmetric segregation and activation of the epidermal growth factor receptor (EGFR) tyrosine kinase, with EGFR subsequently driving both proliferation and increased self-renewal. Defects in asymmetric division were subsequently demonstrated in progenitors that went on to develop tumors, linking defective asymmetric division (leading to an excess of progenitors and too few differentiating cells) to initiation of oligodendroglioma.Zuber J, Shi J, Wang E, Rappaport AR, Herrmann H, Sison EA, et al. RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia. Nature 2011 Aug 3. [Epub ahead of print].Delmore JE, Issa GC, Lemieux ME, Rahl PB, Shi J, Jacobs HM, et al. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell 2011;146:904–17.Myc plays a central role in many cancers, yet targeted efforts to block transcriptional activation by myc have generally been unsuccessful. Myc-driven transcription is associated with increased histone lysine side-chain acetylation. Acetylated histones then recruit proteins with acetyl-lysine binding (bromo) domains to facilitate recruitment of transcriptional activators. Zuber and colleagues identified JQ1, a small-molecule inhibitor of the BET subfamily of bromodomains, demonstrating activity against myc, with associated efficacy in treating acute myeloid leukemia. Building on this result, Delmore and colleagues demonstrated that JQ1 disrupted myc-dependent transcription, arresting growth of myc-driven multiple myeloma. In addition, JQ1 led to depletion of myc itself due to the unexpected finding that myc transcription was itself dependent on BET bromodomains. Thus, blockade of protein-protein interactions within the myc signaling network shows potential for treatment of myc-dependent cancers.Spitz MR, Gorlov IP, Amos CI, Dong Q, Chen W, Etzel CJ, et al. Variants in inflammation genes are implicated in risk of lung cancer in never smokers exposed to second-hand smoke. Cancer Discovery 2011;1:420–9.Although 85% of lung cancers occur in smokers, little is known about other causes of lung cancer, apart from a family history or passive inhalation of carcinogens from passive smoking. Because there is a strong link between chronic lung inflammation and cancer susceptibility, it could be argued that an inherited predisposition to inflammatory disease might be found in nonsmokers with lung cancer. To investigate this hypothesis, Spitz and colleagues evaluated over 11,000 single-nucleotide polymorphisms (SNP) in DNA from 2 independent cohorts of lung cancer patients who had never smoked and in matched control subjects. Of particular interest, and replicated significantly in the 2 different cohorts, was an intronic SNP in the ACVR1B gene. ACVR1B belongs to the TGF-β superfamily and codes for a synonymous protein, also known as ALK-4. This protein may contribute to the resolution of inflammation and initiation of airway remodeling. Hence, an inflammatory lung microenvironment, whether caused by passive smoking, allergies, or chronic infection, may be necessary for the risk from this SNP to be exposed. These findings require further replication and functional validation; however, together with epidemiologic data, they suggest that inflammation may be a common factor in lung cancers.Bertotti A, Migliardi G, Galimi F, Sassi F, Torti D, Isella C, et al. A molecularly annotated platform of patient-derived xenografts (‘xenopatients’) identifies HER2 as an effective therapeutic target in cetuximab-resistant colorectal cancer. Cancer Discovery; Published OnlineFirst September 2, 2011;doi:10.1158/2159-8290.CD-11-0109.As is the case with many other common cancer types, colorectal cancer is not a homogeneous disease but a number of malignancies with different molecular pathologies and natural histories. Thus, molecular-based cancer treatments would be anticipated to be efficacious in only a fraction of patients, with the challenge being, then, to identify those patients who are most likely to benefit. One direct way to achieve this end would be to test a battery of new treatments on each tumor when it is surgically resected. Bertotti and colleagues took this approach with prospective randomized studies of human colorectal cancer liver metastases directly transferred into immune-deficient mice—so-called “xenopatients,” resulting in morphologic and genomic features of the original patients' tumors being retained after serial passage in mice. A validation trial demonstrated that the xenopatients responded to the anti-epidermal growth factor receptor (EGFR) antibody cetuximab with response rates that were analogous to those seen clinically. Based on these findings, predictive biomarkers of response were identified. In addition, HER2 amplification was identified in less than 3% of unselected tumors but in 36% of cetuximab-resistant xenopatients. Finally, in a proof-of-concept multiarm study, the authors demonstrated that a combination of HER2 and EGFR inhibition provided long-lasting tumor regression. Although murine genetic cancer models are increasingly accepted as the gold standard in preclinical experiments, especially those evaluating neoplastic cell-extrinsic mechanisms, this study demonstrates the utility of human tumors grown in immune-deficient mice as clinical mimics that provide a platform for discovery of novel biomarkers and predictive classifiers for better stratification of patients. It is important to note, however, that this approach is unlikely to be informative for evaluation of biologically based therapies interfering with interactions between malignant cells and their supportive nonmalignant microenvironment.Balachandran VP, Cavnar MJ, Zeng S, Bamboat ZM, Ocuin LM, Obaid H, et al. Imatinib potentiates antitumor T cell responses in gastrointestinal stromal tumor through the inhibition of Ido. Nat Med 2011;17:1094–100.Inactivation of oncogenes can elicit oncogene addiction through direct effects on tumor cells, a response involving proliferative arrest, apoptosis, and differentiation/senescence, as well as effects on the host tumor microenvironment, including angiogenesis and altered regulation of innate and adaptive immunity. Balachandran and colleagues report that imatinib, a tyrosine kinase inhibitor, contributes to regression of gastrointestinal stromal tumors not only through direct effects on neoplastic tumor cells but also through modulation of T-cell activation. These results enhance our understanding of how targeted therapies contribute to tumor regression, suggesting that these agents not only influence the biology of malignant tumor cells but also modulate recruited or activated host cells. This information expands upon the notion that cancer therapies mediate their activity in part through effects on the tumor microenvironment, implying that the modulation of the host immune system may cooperate with targeted therapies to induce tumor regression. However, it is also possible that the potential anticancer activity of some therapeutics is being significantly impeded as they may also be antagonizing host immune-mediated antitumor mechanisms. The model described by these authors should help to define these mechanisms to maximize the therapeutic response of targeted therapies.Note: Breaking Advances are written by Cancer Research Editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.