New Agent Targeting Epigenetic Modifications Shows Activity in Advanced Cancer

“In a dose-escalation phase I study reported in The Lancet Oncology, Reid et al found that RRx-001, a representative of a new class of compounds called dinitroazetidines (sourced from the aerospace industry) that act on the tumor microenvironment, had activity in advanced cancers and a promising safety profile. RRx-001 is activated by hypoxia and induces generation of reactive oxygen and nitrogen species that can epigenetically modulate DNA methylation, histone deacetylation, and lysine demethylation.

“In the study, 25 patients with advanced, malignant, incurable solid tumors from the University of California, San Diego, and Sarah Cannon Research Institute received intravenous infusions of RRx-001 at increasing doses of 10 mg/m², 16.7 mg/m², 24.6 mg/m², 33 mg/m², 55 mg/m², and 83 mg/m² once or twice weekly for ≥ 4 weeks.”

Tracer Could Indicate Radiation Benefit to Patient

“A world-first radiotherapy treatment trial by University of WA researchers could have a major impact on the quality of life for mesothelioma patients.

“Funded by an almost $100,000 Cancer Council WA grant, the research team is exploring why some patients respond to radiotherapy treatment while others don’t, as well as developing tests to predict whether patients will respond to avoid people being treated unnecessarily.”

New Test Could Accurately Predict Prostate Cancer Recurrence

“Researchers have created a test that they say can predict whether a man is at high risk of prostate cancer recurrence.

“The research team, led by Prof. Robert Bristow of the Princess Margaret Cancer Centre and the University of Toronto, both in Canada, presented their findings at the 33rd conference of the European Society for Radiotherapy and Oncology (ESTRO33) in Vienna, Italy.

“For men with cancer confined to the prostate, surgery and precision radiotherapy are the primary treatments. However, Prof. Bristow explains that during initial treatment, whether the cancer has spread outside the prostate often goes undetected. This means the cancer will return in 30-50% of patients.”

Reprogramming Metabolism with Metformin Improves Tumor Oxygenation and Radiotherapy Response

“Purpose: Tumor hypoxia is a negative prognostic factor in multiple cancers, due in part to its role in causing resistance to radiotherapy. Hypoxia arises in tumor regions distal to blood vessels as oxygen is consumed by more proximal tumor cells. Reducing the rate of oxygen consumption is therefore a potential strategy to reduce tumor hypoxia. We hypothesized that the anti-diabetic drug metformin, which reduces oxygen consumption through inhibition of mitochondrial complex I, would improve radiation response by increasing tumor oxygenation. Experimental Design: Tumor hypoxia was measured in xenografts before and after metformin treatment using 2-nitroimidazole hypoxia markers quantified by immunohistochemistry (IHC), flow cytometry and positron emission tomography (PET)-imaging. Radiation response was determined by tumor growth delay and clonogenic survival in xenografts with and without administration of metformin. The impact of metformin use on outcome was assessed in 504 localized prostate cancer patients treated with curative-intent, image-guided radiotherapy (IGRT) from 1996 to 2012. Three-year biochemical relapse-free rates were assessed using the Kaplan-Meier method. Results: Metformin treatment significantly improved tumor oxygenation in two xenograft models as measured by IHC, flow cytometry and PET imaging. Metformin also led to improved radiotherapy responses when mice were administered metformin immediately prior to irradiation. Clinically, metformin use was associated with an independent and significant decrease in early biochemical relapse rates (p=0.0106). Conclusion: Our data demonstrate that metformin can improve tumor oxygenation and response to radiotherapy. Our study suggests that metformin may represent an effective and inexpensive means to improve radiotherapy outcome with an optimal therapeutic ratio.”

Hypoxia Induces Phenotypic Plasticity and Therapy Resistance in Melanoma via the Tyrosine Kinase Receptors ROR1 and ROR2

“An emerging concept in melanoma biology is that of dynamic, adaptive phenotype switching, where cells switch from a highly proliferative, poorly invasive phenotype to a highly invasive, less proliferative one. This switch may hold significant implications not just for metastasis, but also for therapy resistance. We demonstrate that phenotype switching and subsequent resistance can be guided by changes in expression of receptors involved in the non-canonical Wnt5A signaling pathway, ROR1 and ROR2. ROR1 and ROR2 are inversely expressed in melanomas and negatively regulate each other. Further, hypoxia initiates a shift of ROR1-positive melanomas to a more invasive, ROR2-positive phenotype. Notably, this receptor switch induces a 10-fold decrease in sensitivity to BRAF inhibitors. In melanoma patients treated with the BRAF inhibitor, Vemurafenib, Wnt5A expression correlates with clinical response and therapy resistance. These data highlight the fact that mechanisms that guide metastatic progression may be linked to those that mediate therapy resistance.”

Drug Activated When Oxygen is Low Could Target Melanomas

Many tumors have oxygen-depleted areas; and the cells there are more likely to invade, spread, and resist current treatments. But a new experimental cancer drug, called TH-302, is activated when oxygen is low. In a phase I clinical trial of 34 people with melanoma, TH-302 shrank tumors in 7 people and kept tumors from getting worse in 12 more people. Now, researchers have begun a phase II trial that will include up to 40 people with melanoma. This drug could also treat a variety of cancers and phase III trials are currently underway for soft tissue sarcoma and pancreatic cancer.

Targeting Autophagy as a Potential Therapeutic Approach for Melanoma Therapy

“Melanoma, occurring as a rapidly progressive skin cancer, is resistant to current chemo- and radiotherapy, especially after metastases to distant organs has taken place. Most chemotherapeutic drugs exert their cytotoxic effect by inducing apoptosis, which, however, is often deficient in cancer cells. Thus, it is appropriate to attempt the targeting of alternative pathways, which regulate cellular viability. Recent studies of autophagy, a well-conserved cellular catabolic process, promise to improve the therapeutic outcome in melanoma patients. Although a dual role for autophagy in cancer therapy has been reported, both protecting against and promoting cell death, the potential for using autophagy in cancer therapy seems to be promising. Here, we review the recent literature on the role of autophagy in melanoma with respect to the expression of autophagic markers, the involvement of autophagy in chemo- and immunotherapy, as well as the role of autophagy in hypoxia and altered metabolic pathways employed for melanoma therapy.”

HIF1α and HIF2α independently activate SRC to promote melanoma metastases

Malignant melanoma is characterized by a propensity for early lymphatic and hematogenous spread. The hypoxia-inducible factor (HIF) family of transcription factors is upregulated in melanoma by key oncogenic drivers. HIFs promote the activation of genes involved in cancer initiation, progression, and metastases. Hypoxia has been shown to enhance the invasiveness and metastatic potential of tumor cells by regulating the genes involved in the breakdown of the ECM as well as genes that control motility and adhesion of tumor cells…”