The customizable approach, which the researchers call RASER, relies on just two proteins: The first is activated in the presence of an "always on" growth signal often found in cancer cells, and the second carries out a researcher-programmed response, such as triggering the expression of genes involved in cell death.
Although the experiments were confined to cells grown in the laboratory, the researchers believe the results could lead to a new type of cancer therapy in which synthetic proteins deliver highly targeted and customizable treatments to sidestep the sometimes devastating side effects of current options. Cancer cells arise from faulty signals that allow them to grow inappropriately, so we've hacked into cancer cells to redirect these faulty signals to something useful.
A paper describing the work will be published May 2 in Science. Lin is the senior author. Former graduate student Hokyung Chung, PhD, is the lead author. Many cancers rely on a series of signals that originate from proteins called receptors that span the membrane of the cell.
These signaling cascades, or pathways, are used by healthy cells to grow in response to external cues, for example during development or recovery from injury. Often, however, these receptor proteins are mutated or overexpressed in cancer cells in ways that render the receptor protein "always on," providing the cell with constant, unwarranted signals for growth. The researchers focused on two receptors, EGFR and HER2 -- members of a family of receptors called the ErbB receptors -- that often drive the growth of brain, lung and breast cancers.
HER2, for example, is targeted by Herceptin in breast cancer. Many common anti-cancer drugs, including Herceptin, work by blocking the cascade of signals triggered by receptor activation. Unfortunately, however, these drugs have no way to discriminate between cancerous cells, in which the pathway is always activated, and healthy cells going about their business as usual. That's where Lin and his team come in. But we've not had a way to do it until recently.
Chung and her colleagues designed a synthetic protein consisting of two natural proteins fused together -- one that binds to active ErbB receptors and another that cleaves a specific amino acid sequence. They then engineered a second protein that binds to the inner surface of the cell membrane and contains a customizable "cargo" sequence that can carry out specific actions in the cell. When the first protein binds to an active ErbB receptor, it cuts the second protein and releases the cargo into the interior of the cell.
In this way, the system produces an effect only in cancer cells, and we can convert the always-on state of the receptor into different outcomes through the choice of cargo protein. After several rounds of tinkering, the team saw that their RASER system, which stands for "rewiring of aberrant signaling to effector release," was highly specific for cancer cells dependent on ErbB receptor activity.
For their first test they chose to use a protein involved in triggering cell death as the RASER cargo. The team compared the RASER system to two therapies currently used for metastatic breast cancer -- a chemotherapy regimen and a drug that blocks ErbB activity -- on several types of cultured cells: breast and lung cancer cells in which the ErbB pathway was overly active; breast cancer cells in which ErbB activity was normal; and noncancerous breast and lung cell lines.
The researchers found that the traditional chemotherapy regimen of carboplatin and paclitaxel killed all the cells indiscriminately.
The effect of the ErbB pathway inhibitor on the viability of the cells varied and did not reliably correlate with ErbB pathway activity levels. While much work remains to be done to learn whether RASER is effective in human tumors, the researchers are excited about the possibilities of re-engineering the system to recognize other receptors mutated in cancers and swapping the cargos to achieve different outcomes. Challenges include learning how best to deliver synthetic proteins into tumors and understanding how the immune system might react to RASER.
Cancer Treatment and Research Communications
But Lin is optimistic. RASER is both customizable and generalizable, and it allows us for the first time to selectively target cancer cells while sparing normal signaling pathways. Review Article 2 Oct Nature. In this Review, the mechanisms by which epi-drugs can modulate the sensitivity of cancer cells to other diverse forms of anticancer therapy are described, and completed and ongoing clinical trials relating to combination therapies incorporating epi-drugs are discussed.
In addition, clinical trial designs and drug development strategies aimed at optimizing the development of such combinations are outlined. This Review describes small molecules and oligonucleotides that modulate the spliceosome and are now in clinical trials for the treatment of cancer. Nucleic acid sensors NASs are essential for the preservation of cellular and organismal homeostasis, with dysregulated NAS signalling contributing to the pathology of a variety of conditions, including infectious diseases, autoimmune disorders and malignancy. Here, Galluzzi and colleagues discuss recent progress in the development of therapeutic NAS modulators and highlight obstacles faced in their clinical development.
Colorectal cancer CRC is one of the most common cancers worldwide. This Review describes the role of microorganisms in colorectal carcinogenesis, and the potential clinical translation of the gut microbiota as a biomarker for CRC diagnosis and prognosis, and as an approach for disease prevention and to improve therapy.
Breast cancer is the most frequent malignancy in women worldwide. Patients are managed on the basis of the key molecular and histological features underpinning their disease and its stage. This Primer discusses these issues, covering both early and advanced disease. Aneuploidy contributes to tumorigenesis, but the underlying processes are not well understood.
Department of Cancer Biology
This Review explains the context dependency of aneuploidy in cancer and discusses its clinical potential as a prognostic marker and a therapeutic target. HER2-targeted therapies have dramatically improved the outcomes in women with HER2-positive breast cancer. Furthermore, genetic sequencing studies have revealed HER2 alterations in a range of other cancers, including gastric cancer, colorectal cancer and non-small-cell lung cancer. In this Review the authors describe the available data on HER2-targeted therapies beyond breast cancer. Despite promising responses in a minority of patients with cancer, considerable scope remains to improve the efficacy of both immune-checkpoint inhibitors and epigenetic drugs, with one potential strategy involving the combination of these two types of treatment.
Here, the authors describe the mechanisms underlying the synergy between immune-checkpoint inhibitors and epigenetic drugs and discuss the ongoing clinical development of such combinations. Fanconi anaemia, ataxia telangiectasia, Nijmegen breakage syndrome and Bloom syndrome are rare, clinically distinct, chromosome instability syndromes.
This Primer describes the understanding of the genetic and molecular basis of these disorders, including the relationship of the defects to the predisposition to cancer.
This Opinion discusses the effects of dietary factors on tumour growth and progression through changes in nutrient availability and metabolism, proposing an experimental framework for the investigation of the connections between diet and tumour metabolism. Perspective 17 Sep Nature Reviews Cancer.
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- Synthetic biology used to target cancer cells while sparing healthy tissue -- ScienceDaily.
The research autopsy is an underused approach to investigate fundamental questions in cancer biology. This Review discusses the rationale for using research autopsies in cancer research, highlighting how this approach has improved knowledge of cancer biology and its tremendous potential to inform future precision medicine strategies. The interactions between tumours and the immune system are highly complex.
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This article discusses methods — primarily computational tools — for characterizing diverse aspects of cancer—immune cell interactions, including antigen presentation, T cell repertoires and heterogeneity in cell types and cell states. The Review particularly highlights the insights from single-cell data from both sequencing technologies and in situ imaging of tissues.
The impact of fungi on human health is under-studied and underappreciated. One genus of fungus, Malassezia, has now been linked to the progression of pancreatic cancer. Morris IV et al. Three studies show that synaptic interactions between neurons and glioma cells or cells of breast-cancer-to-brain metastases may promote tumour growth.
In this Comment, the author, a cancer researcher and breast cancer survivor, discusses her experience as a patient with cancer and how it influenced her approach to research. Comment 1 Oct Nature Reviews Cancer. In this Viewpoint article, Nature Reviews Immunolog y invites 18 experts to discuss the nature of T cell exhaustion. How should T cell exhaustion be defined and what are the developmental relationships between exhausted T cell subsets? The contributors share their thoughts on key recent developments in the field. Viewpoint 30 Sep Nature Reviews Immunology.
Using high-resolution proteomics to analyse clinical samples from patients with advanced melanoma, Harel et al. The ideal first-line treatment of cisplatin-ineligible patients with metastatic urothelial carcinoma mUC remains unknown pending results of randomized trials.
Cancer Biology | Cancer Center | Medical College of Wisconsin
Although mUC tumours are sensitive to chemotherapy, response durations are short. Circulating cell-free DNA cfDNA is shed in the bloodstream by normal and tumor cells and is a valuable liquid biopsy tool. This protocol describes a low-input approach to enrich methylated DNA fragments from cfDNA and prepare sequencing libraries. Protocol Extension 30 Aug Nature Protocols.
Here, the authors describe a marker-independent, unbiased lineage-tracing method to quantitatively assess stem cell function and tumor growth dynamics in unperturbed tumor tissue.