Breaking Insights Highlights from Recent Cancer Literature

Cancer Research Breaking Insights Highlights from Recent Cancer Literature

Photodynamic Priming Improves Drug Delivery

Physiological barriers to drug delivery reduce survival outcomes in cancer patients. Huang and colleagues present preclinical evidence that a subtumoricidal photodynamic priming (PDP) strategy can relieve drug delivery barriers in the tumor microenvironment to improve the therapeutic index of a nanoformulated cytotoxic drug. PDP simultaneously increased the local concentration in tumors of a topoisomerase inhibitor, irinotecan, while also increasing the duration of drug exposure above a critical therapeutic threshold. PDP also attenuated surges in CD44 and CXCR4, which mediate chemoresistance, leading to superior treatment outcomes in orthotopic models of pancreatic ductal adenocarcinoma (PDAC). Expert Commentary: This study offers preclinical proof of concept for the effectiveness of PDP to minimize risks of relapse, progression, and drug resistance, and to extend survival. Building on the recent clinical advances using photodynamic therapy for locally advanced PDAC patients, these ﬁndings offer prospects to design new PDP-based approaches that enhance drug accessibility while minimizing treatment-induced selection for resistance, without added side effects.

Huang HC, Rizvi I, Liu J, Anbil S, Kalra A, Lee H, et al. Photodynamic priming mitigates chemotherapeutic selection pressures and improves drug delivery. Cancer Res 2017;78:558–71.

NFS1 Is Essential for Tumorigenesis in Oxygen-Rich Tissues

Environmental nutrient levels inﬂuence not only tumor metabolism but growth and metastatic potential. Alvarez and colleagues demonstrate an essential role for the iron-sulfur cluster biosynthetic enzyme NFS1 in primary tumor progression and in metastases to relatively oxygen-rich tissues, such as the lung. As such, NFS1 was ampliﬁed and/or overexpressed in lung adenocarcinomas. NFS1 is required for proper synthesis of iron-sulfur clusters, which are necessary for the function of multiple essential enzymes and are sensitive to oxidative stress. In the absence of NFS1, they observed activation of the iron-starvation pathway, which primed the tumor for ferroptosis in the presence of reactive oxygen species (ROS).

Expert Commentary: These studies not only elucidate a novel essential mechanism for tumorigenesis and metastases to oxygen-rich tissues but suggest a novel therapeutic strategy of targeting the NFS1 pathway to sensitize these cells to ROS, leading to ferroptosis. (Image courtesy of Wikimedia Commons.)

Alvarez SW, Sviderskiy VO, Terzi EM, Papagiannakopoulos T, Moreira AL, Adams S, et al. NFS1 undergoes positive selection in lung tumours and protects cells from ferroptosis. Nature 2017;551:639–43.

A Two-Hit Hypothesis of Drug Resistance?

The importance of Hedgehog (HH) signaling in many cancers, including medulloblastoma, has led to the development of inhibitors targeting HH pathway components such as the G-protein-coupled receptor, smoothened (SMO). The long-term efﬁcacy of SMO inhibitors, however, is limited by the emergence of drug resistance. Zhao and colleagues developed a novel transposon mutagenesis screen in a mouse medulloblastoma model to identify mechanisms of resistance to SMO inhibitors. They observed loss of function in genes involved in cilia formation, especially Ofd1, corroborated in clinical data sets. Loss of primary cilia, expected to abrogate HH signaling, paradoxically led to activated HH signaling. They demonstrated that impaired processing decreased GLI2 transcriptional activity, resulting in HH activation. These slow-growing "persister" cells acquired additional genetic alterations such as loss of Suppressor of fused, the negative regulator of SMO, that synergized with loss of primary cilia to induce a proliferative state.

Expert Commentary: These ﬁndings describe a novel form of resistance to SMO inhibitors—loss of cilia formation. Cells with mutations in ciliogenesis genes exist in a "persister" state and evolve into a rapidly proliferative state upon acquiring second hits. (Image courtesy of Wikimedia Commons.)

Zhao X, Pak E, Ornell KJ, Pazyra-Murphy MF, MacKenzie EL, Chadwick EJ, et al. A transposon screen identiﬁes loss of primary cilia as a mechanism of resistance to SMO inhibitors. Cancer Discov 2017;7;1436–49. www.aacrjournals.org 311

Myc and Ras Cooperate through the Tumor Microenvironment

Previous work has shown that Myc and KRas mutations cooperate during NSCLC progression, however, how they do so is unclear. Using an inducible Myc construct in a KRas mutant mouse lung tumor model, Kortlever and colleagues show that while mutant KRas is sufﬁcient for lung adenoma formation, Myc is required for adenocarcinoma progression. Myc expression resulted in increased inﬂammation and angiogenesis, as well as suppression of immune surveillance, and these processes occurred rapidly. The regulation of the tumor microenvironment by Myc was primarily controlled via the expression and secretion of tumor cell-derived IL23 and CCL9. Further, these changes to the tumor microenvironment were rapidly reversed when Myc expression was turned off, or when IL23 and CCL9 activity was attenuated.

Expert Commentary: Myc cooperates with KRas mutations by orchestrating a rapid reprogramming of the tumor microenvironment, which is required for adenocarcinoma formation. (Imagecourtesyof Wikimedia Commons.)

Kortlever RM, Sodir NM, Wilson CH, Burkhart DL, Pellegrinet L, Brown Swigart L, et al. Myc cooperates with RAS by programming inﬂammation and immune suppression. Cell 2017;171:1301–15.

Personalizing Therapy for High-Risk Group 4 Medulloblastoma

Badodi and colleagues generated a BMI1-driven Sleeping Beauty transposon-based murine model to demonstrate that the polycomb protein BMI1 cooperates with loss of the ATP-dependent helicase protein CHD7 to initiate medulloblastoma (MB). Analysis of human survival data identified poor survival in group 4 MB tumors with BMI1high and CHD7low expression. In vitro, increased proliferation with CHD7 knockdown was dependent on BMI1. Gene expression profiling from CHD7 knockdown cells identified enrichment for polycomb repressor complex–responsive genes. Finally, pathway analysis of BMI1high/CHD7low group 4 MB revealed enrichment for ERK signaling, and CHD7 knockdown activated ERK1/2.

Expert Commentary: Group 4 medulloblastoma is the most common but least understood subgroup, with a paucity of actionable mutations. This study provides the ﬁrst indication that ERK activation is important in group 4 MB and suggests a rational treatment paradigm for a subset of high-risk patients. (ImagecourtesyofWikimediaCommons.)

Badodi S, Dubuc A, Zhang X, Rosser G, Da Cunha Jaeger M, Kamela-Smith MM, et al. Convergence of BMI1 and CHD7 on ERK signaling in medulloblastoma. Cell Rep 2017;21:2772–84.

Glucose Feeds the TCA Cycle via Circulating Lactate

Metabolic reprograming is one of the hallmarks of cancer and includes increased production of substrates essential for the proliferation of cancer cells and for synthesis of biomass. Hui and colleagues used 13C-labeled nutrients to evaluate turnover ﬂux of different circulating carbon metabolites in mice. Quantitative analysis demonstrated that lactate can be the major source of carbon for the Krebs cycle and thus for energy in most tissues as well as in tumors. Their work shows that by having glucose feed the TCA cycle via circulating lactate, the housekeeping function of ATP production is decoupled from glucose catabolism.

Expert Commentary: This study demonstrates that lactate can be the major carbon source in both normal cells as well as in tumors, which in turn allows glucose metabolism to serve more advanced purposes of the organism. (Image courtesy of Wikimedia Commons.)

Hui S, Ghergurovich JM, Morscher RJ, Jang C, Teng X, Lu W, et al. Glucose feeds the TCA cycle via circulating lactate. Nature 2017;551:115–8.

Note: Breaking Insights 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.

312 Cancer Research

Cancer Res 2018;78:311-312.

Updated version Access the most recent version of this article at: http://cancerres.aacrjournals.org/content/78/2/311

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