Arming the Immune System to Fight Cancer

Cancerous tumors are formed when the immune system is unable to remove these diseased cells. Once immune cells capable of killing tumors are activated specifically, they can see tumors that were previously invisible to the immune system. When an immune system is working properly, diseased cells are captured and killed. To date, some researchers have unveiled the cancer’ evasion mechanism and recruited immune system to fight cancer.

Events in Cancer immunology

Events in Cancer immunology

Dr. Freeman’s lab In the Dana-Farber Cancer Institute develops an extensive body of knowledge regarding inhibitory signals conveyed by tumor cells via the programmed death 1 (PD-1) receptor and its ligand PD-L1. Interaction between PD-1 receptor and its ligand deactivates CD8 T cells and inhibits their capacity to kill tumor cells and make cytokines that recruit other immune cells.

Researchers in the Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute eradicates solid tumors in laboratory mice using a novel combination of two targeted agents (a mTOR inhibitor and a CD4 antibody). These two synergistic therapies increase the immune system’s “memory” and ability to recognize tumors, ultimately allowing solid tumors to act as their own cancer-fighting vaccine.

Dr. Lee’s team at Roswell Park Cancer Institute explores two receptors (called CD80 and CD86) expressed on the surface of dendritic cells that trigger the cells to make either immune-stimulating factors or immune-suppressive factors. They defined the intracellular pathways by which the receptors triggered each response.

Fight against cancer

Deep insight into evasion mechanisms of solid tumors contributes to employing new therapeutic strategy to fight cancer. Actually, immune system is harnessed to specifically target tumour cells owing to tumour-specific immunological memory.

Åsa Lindgren, a researcher from the Department of Microbiology and Immunology ,finds that Activation of the NK cells can play a key role in stopping tumors from developing, and that reduced NK-cell activity can increase the risk of cancer developing. These findings are hoped to develop new ways of diagnosing and treating stomach cancer.

Researchers at the University of Calgary’s Hotchkiss Brain Institute (HBI) make a great discovery that amphotericin B (AmpB) as a drug is able to re-activate those immune cells and reduce brain tumor growth, thereby increasing the lifespan of mice two to three times.

Reference:

Foxp3 T cells inhibit antitumor immune memory modulated by mTOR inhibition. Cancer Research, 2014; DOI: 10.1158/0008-5472.CAN-13-2928

Programmed death-1 (PD-1) is a marker of germinal center-associated T cells and angioimmunoblastic T-cell lymphoma. Am J Surg Pathol. 2006 Jul;30(7):802-10.

Novel Regulation of CD80/CD86-induced Phosphatidylinositol 3-Kinase Signaling by NOTCH1 Protein in Interleukin-6 and Indoleamine 2,3-Dioxygenase Production by Dendritic Cells. Journal of Biological Chemistry, 2014; 289 (11): 7747

Marian R.Glancy

Oncology Goes Ahead for Deals and Dollars

According to statistics, dealmaking partnerships shrank to 301 deals in 2013, down one-fifth from 2012. However, oncology persists as a dominant area with 84 deals, in which biotech startups cooperates with academic institute focusing on technology platform rather than a single compound.

 As data shown, it is the big-ticket deals in oncology, and deal making covers extensively broad spectrum, although top ten records the megadeals and the EP Vantage data focuses on deals around products in Phase 1 to Phase 3.

Deals by business area, 2013(Source: SciBx: Science-Business eXchange)

Deals by business area, 2013(Source: SciBx: Science-Business eXchange)

 Commercial returns in Cancer immunotherapy

Since FDA approved Dendreon’s Provenge for treating prostate cancer and Bristol-Myers’s Yervoy for melanoma treatment. Immunotherapy are increasingly seen as a fourth category of oncology treatment, added to surgery, radiotherapy and chemotherapy.

In a cancer immunotherapy deal announced in March 2013, Celgene established tie-up with the gene-therapy bluebird bio,. In the US$225 million-plus deal, bluebird will be applying its technology to genetically modify a patient’s own T cells, priming them to target and destroy tumor cells.

In another cancer immunotherapy deal that closed in 2012, Colby Pharmaceutical, a privately owned company based in San Jose, California, acquired the immunotherapy assets of MannKind, including a Phase 1 melanoma vaccine that uses intra–lymph node injection to target cancer antigens directly at T cells.

Insight into academic-private partnerships 2013

Harvard University was one of the most active deal makers without focusing on oncology in 2013 (shown by below table). By contrast, University of Texas System processed 3 deals, belonging entirely to oncology. In the 25 deals listed, 8 deals were engaged in oncology. Additionally, both Johns Hopkins University and KU Leuven broke into the top 5 in 2013. Correspondingly, University College London and Broad Institute of MIT and Harvard dropped out of the top 5.

Academic-private partnerships 2013

Source: SciBx: Science-Business eXchange

Source: SciBx: Science-Business eXchange

Reference:

1. Academic-industry partnerships 2013. Nature Biotechnology 2014. doi:10.1038/nbt.2861

Marian R.Glancy

Unravel the mystery about resistance to BRAF inhibition in melanoma

Melanoma is the most aggressive type of skin cancer and the leading cause of death from skin disease. Half of melanoma patients with the BRAF mutation have a positive response to treatment with BRAF inhibitors, but nearly all of those patients develop resistance to the drugs and experience disease progression. To overcome this disease, many investigators attempted to solve the problem of BRAF-inhibitor resistance leading to medically ineffective treatment.

Sensitive and resistance to BRAF inhibition in melanoma

Sensitive and resistance to BRAF inhibition in melanoma

A research indicates that the root of resistance to BRAF inhibitors may lie in a never-before-seen autophagy mechanism induced by the BRAF inhibitors in many cases. Autophagy is a process by which cancer cells recycle essential building blocks to fuel further growth. Block this pathway with the antimalarial drug hydroxycholoroquine (HCQ), and the BRAF inhibitors will be able to do their job better.

Another research interprets why some BRAF or MEK inhibitor-resistant melanoma patients may regain sensitivity to these drugs after a ‘drug holiday’. According to analysis, 6 out of 16 melanoma tumours acquired EGFR expression after the development of resistance to BRAF or MEK inhibitors. Suppression of sex determining region Y-box 10 (SOX10) in melanoma is found to cause activation of TGF-β signalling, thus leading to upregulation of EGFR and platelet-derived growth factor receptor-β (PDGFRB), which confer resistance to BRAF and MEK inhibitors. In a heterogeneous population of melanoma cells having varying levels of SOX10 suppression, cells with low SOX10 and consequently high EGFR expression are rapidly enriched in the presence of drug, but this is reversed when the drug treatment is discontinued. Additionally, investigators find evidence for SOX10 loss and/or activation of TGF-β signalling in 4 of the 6 EGFR-positive drug-resistant melanoma patient samples.

With the application of value, Moffitt researchers found that using two inhibitors (Mekinist [trametinib] and Tafinlar[dabrafenib]) to block different growth pathways during treatment prevented resistance in patients with BRAF mutation. The combination of these two inhibitors, as a newly FDA-approved therapy, is one of the biggest advancements in melanoma treatment in the past 30 years. From a clinical perspective, 76 percent of patients achieve success in the treatment of the Mekinist and Tafinlar combination, and this therapy reduces the incidence and severity of some of the toxic effects patients experience when the drugs is used alone.

Reference:

1. Reversible and adaptive resistance to BRAF(V600E) inhibition in melanoma. Nature. 2014 Apr 3;508(7494):118-22.

2. Combined BRAF and MEK Inhibition in Melanoma with BRAF V600 Mutations. New England Journal of Medicine, 2012; 367 (18): 1694 DOI: 10.1056/NEJMoa1210093

3. Targeting ER stress–induced autophagy overcomes BRAF inhibitor resistance in melanoma. Journal of Clinical Investigation, 2014; DOI: 10.1172/JCI70454

Marian R.Glancy

To target oncogenes: An Achilles’ heel of Cancer

An oncogene is a kind of abnormal gene that predisposes cells to develop into cancers. Unlike normal genes, oncogenes are altered in a way that keeps them stuck in a state of constant activity. That uninterrupted action helps drive the uncontrolled growth that underlies tumors. One measure scientists take to inhibit this process is that small inhibitory RNAs are designated for silencing oncogenes.

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The activation of oncogenes involves genetic changes to cellular proto-oncogenes. The consequence of these genetic alterations is to confer a growth advantage to the cell. Three genetic mechanisms activate oncogenes in human neoplasms: mutation, gene amplification, and chromosome rearrangements. These mechanisms result in either an alteration of proto-oncogene structure or an increase in proto-oncogene expression. Because neoplasia is a multistep process, more than one of these mechanisms often contribute to the genesis of human tumors by altering a number of cancer-associated genes.

Against potential Achilles’ heel in the oncogene

A XBP1 gene implicated in progression and relapse of deadly breast cancer finding points to potential Achilles’ heel in triple negative breast cancer(TNBC), and targeting this gene may be a new approach to treating the disease. Investigators find that interactions between XBP1 and another transcriptional regulator, HIF1-alpha, spurs the cancer-driving proteins. Silencing XBP1 in the TNBC cell lines reduces the tumor cells’ growth and other behaviors typical of metastasis.

Another study shows that a critical gene called oncogene is turned off by RNA interference, and it increases survival rates in mice suffering from glioblastoma. The therapeutic, based on nanotechnology, is nimble enough to cross the blood-brain barrier and get to the brain tumor. Once there, it flips the switch of the oncogene to “off,” silencing the gene.

Reference:

1.  Mechanisms of oncogene activation. Holland-Frei Cancer Medicine. 6th edition.

2. XBP1 promotes triple-negative breast cancer by controlling the HIF1α pathway. Nature, March 2014 DOI: 10.1038/nature13119

3. Spherical Nucleic Acid Nanoparticle Conjugates as an RNAi-Based Therapy for Glioblastoma. Science Translational Medicine, 2013; 5 (209): 209ra152 DOI: 10.1126/scitranslmed.3006839

Marian R.Glancy

Childhood cancer: Current challenge and a comprehensive care

A new report from the American Cancer Society says in 2014, an estimated 15,780 new cases of cancer will be diagnosed and 1960 deaths will occur among children and adolescents aged birth to 19 years. Annual incidence of cancer from birth to age 19 is 18.8 per 100,000; approximately 1 in 285 children will be diagnosed with cancer before age 20. Although some advances in surgical techniques, delivery of radiation therapy, and use of chemotherapy improve childhood cancer survivors in survival, children treated for many cancers are at high risk of long-term health issues, such as seizures, blindness, and hearing loss.

Childhood cancer rates vary by cancer type

Childhood cancer rates vary by cancer type

 (Source: Surveillance, Epidemiology, and End Results Program, 1975-2003)

Some challenges remain in fighting childhood cancer. Unlike adult cancers, only a relatively small percentage of all childhood cancers have known preventable causes. Additionally, A clinician finds it more difficult to early detect cancer in children, because of the similarity of some symptoms to those of more common childhood diseases.

It is therefore likely that Specialized medical care need to be tailored to address these challenges. Children with a predisposition to cancer would be diagnosed with novel screening methods. The doctors can identify tumors sooner in these children, allowing for treatments to be implemented earlier, ultimately leading to improved survival rates. Additionally, more comprehensive data tease out several cancer types to offer a clearer picture of the actual childhood cancer landscape. Tremendous variation in survival and success rates across different childhood cancers can be demonstrated by the above figures .

To achieve a comprehensive care, the integration of palliative care improve quality of life in the pediatric cancer survivors.  Although not affected the eventual outcome, it may relieves the child’s disease symptoms. Focus on quality of life requires 2 things. First, it requires palliative care training for all pediatric specialists, not just those who seek it out. Every pediatric clinician, in partnership with other health care providers and supporters, is capable of addressing the needs of children with cancer and their families. Every childhood cancer journey should start with a plan for specialized medical care, including palliative care. Unfortunately, however, pediatric palliative care teams are not yet available in all settings in which children and families receive their care. Second, we need more research about quality of life for pediatric patients with cancer along the entire cancer care continuum.

 Reference:

1. Because statistics don’t tell the whole story: A call for comprehensive care for children with cancer. CA: A Cancer Journal for Clinicians ,2014

2. Childhood and adolescent cancer statistics, 2014. CA: A Cancer Journal for Clinicians, 2014; DOI: 10.3322/caac.21219

3. Early palliative care for patients with advanced cancer: a cluster-randomised controlled trial. The Lancet, 2014; DOI: 10.1016/S0140-6736(13)62416-2

Marian R.Glancy

To overcome the resistance to EGFR-targeted therapy in cancer

Some patients with metastatic lung ,colorectal or pancreatic cancers initially show positive results from EGFP-targeted therapies, however the resistance to targeted therapies eventually develops. In order to make it effective, researchers attempt to understand what related proteins in a signaling network cause resistance of tumors to EGFR inhibitors. With growing knowledge of resistance pathways appear, we obtain a great chance to develop new mechanism-based inhibitors or joint therapies to prevent therapeutic resistance in tumors.

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Louis Weiner et al discuss how cancer cells activate a network of specific proteins which evade a molecule from being therapeutically in the issue of Science Signal. Treatment by FDA-approved drugs that are designated to shut down the EGFR tend to be inefficient, partly due to involving of some genes in evading cancer cells. He says the essence of drug resistance is evolutionary pressure to survive, and the only way to treat cancer is to disarm some of key “rescue” genes and proteins. by using a screen technique, investigators identified 61 genes that play some role in anti-EGFR drug resistance.

The concept of oncogene addiction was defined by Weinstein in 2002, which highlights the crucial importance of EGFR to tumor cell survival in lung adenocarcinoma. It means that a cancer cell is dependent of a specific oncogenic signaling pathway. For instance. Drugs that inhibit mutant EGFR such as erlotinib turn off this key pathway and result in tumor cell apoptosis.

 A decade later, oncogene-targeted therapies grant a reprieve for patients who are lucky to have been selected driver mutation, and alleviation last years in some cases. For patients with EGFR-mutant lung cancer, tumor responses persist for months which is better than patients without such a mutation.

 Cancer researchers and clinicians should realize the importance of perseverance, creativity and collaboration. Whether tumor resistance is defeated using combinations of drugs, immunotherapy, new dosing strategies or an undiscovered approach, patients cannot benefit from novel therapies soon enough.

Marian R.Glancy

Selective PI3K inhibitors show an effective prospect in the treatment of human multiple myeloma

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Treatments may be used not only to treat and to control the myeloma itself, but also to ease symptoms and complications of the myeloma. Radiotherapy, Bisphosphonates, and Other Supportive Therapies would bring about adverse effects, Such as bone pain and fractures. Thus, developing effective therapies against multiple myeloma (MM) is a pending challenge.

PI3K activation may be correlated with tumor progression and drug resistance, and inhibiting PI3K can induce apoptosis in MM cells. Therefore, inactivation of PI3K is predicted to increase the susceptibility of MM to anticancer therapy. Glauer J, et al demonstrated that a novel class of PI3K inhibitors, BAY80-6946, was highly efficacious in four different MM cell lines, where it induced significant antitumoral effects in a dose-dependent manner. The compound inhibited cell cycle progression and increased apoptosis, and showed convincing in vivo activity against the human AMO-1 and MOLP-8 myeloma cell lines in a preclinical murine model.

Additionally, Munugalavadla V et al indicated that the PI3K inhibitor GDC-0941, combined with existing clinical regimens, exhibited superior activity in multiple myeloma. In vitro, GDC-0941 was synergized with dexamethasone and lenalidomide; in vivo GDC-0941 had anti-myeloma activity and significantly increased the activity of the standard of care agents in several murine tumor models.

These data provide a clear therapeutic prospect for the inhibition of PI3K and provide a rationale for clinical development of GDC-0941 in myeloma.

Marian R.Glancy

Noncanonical Functions of Telomerase and Telomerase-Targeted Cancer Therapies

Telomerase plays a key role in bypassing cellular senescence and maintaining telomere homeostasis, essential properties required for the sustenance and progression of cancer. However, recent researches have uncovered noncanonical properties of telomerase that are independent of its role in telomere extension. The following picture is the human telomerase structure model.

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As we know, telomerase consists of TERT subunit, RNA subunit and a group of accessory protein , repaires chromosomal shrinkage resulting from the “end-replication” problem. It plays the critical role in maintaining the balance between normal cellular differentiation and the aberrant proliferation manifested in carcinogenic transformation.

Recently, researchers proposed a model of the feed-forward regulatory loop underscoring the interaction of TERT with the Wnt/β-catenin and NF-κB signaling pathways during cancer development. Reactivated TERT acts as a transcriptional modulator of Wnt/β-catenin and NF-κB signaling, resulting in the enhanced expression of Wnt and NF-κB target genes that exert cancer-promoting functions such as proliferation, resistance to apoptosis, and chronic inflammation. As Wnt/β-catenin and NF-κB are also transcriptional activators of TERT, the researchers suggest a feed-forward pathway (illustrated by blue arrows) that sustains Wnt/β-catenin and NF-κB–dependent transcription as well as levels of telomerase in cancer cells in a simplified schematic of signaling events.

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 In view of the evidence mentioned earlier linking the noncanonical functions of telomerase to cancer development and progression, targeting telomerase as an anticancer strategy seems to be an effective approach to simultaneously dampen oncogenic signaling pathways that are augmented by telomerase and disrupt the feed-forward regulatory mechanism driving chronic inflammatory/oncogenic responses and sustained telomerase activity in cancers. Furthermore, as telomerase is often upregulated in cancer cells, whereas majority of normal somatic cells have undetectable telomerase activities, telomerase-targeted cancer therapies serve to selectively eliminate tumor cells and avoid the adverse side effects. More and more evidence indicates a compelling rationale for the development of therapeutic approaches that target the noncanonical roles of telomerase, instead of solely relying on conventional small-molecule inhibitors that restrict its enzymatic activity or accessibility/function at telomeres.

 Marian R.Glancy

Reference:

1. Noncanonical functions of telomerase: implications in telomerase-targeted cancer therapies.    Cancer Res. 2014 Mar 15;74(6):1639-44.

2. Structural basis for telomerase catalytic subunit TERT binding to RNA template and telomeric    DNA. Nat Struct Mol Biol. 2010 Apr;17(4):513-8

3. Human telomerase model shows the role of the TEN domain in advancing the double helix for the next polymerization step. Proc Natl Acad Sci U S A. 2011 Jun 7;108(23):9443-8

4. Telomerase modulates Wnt signalling by association with target gene chromatin. Nature. 2009 Jul 2;460(7251):66-72.

5. Wnt/β-catenin signaling regulates telomerase in stem cells and cancer cells. Science. 2012 Jun 22;336(6088):1549-54.

6. Telomerase directly regulates NF-κB-dependent transcription. Nat Cell Biol. 2012 Dec;14(12):1270-81.

Targeting the NF-κB pathway may provide therapeutic benefits to patients with basal-like, triple-negative breast cancer

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Previously study has been shown that, α-catenin could complex with the IκBα protein, and stabilize IκBα by inhibiting its and its association with the proteasome.

Usually, Aberrant activation of NF-κB signaling is found in triple-negative basal-like breast cancer cells, while the cause of this activation has remained elusive,The NF-κB pathway can be activated by a variety of factors. Activated NF-κB regulates kinds of target genes. Aberrant activation of NF-κB signaling is associated with various human cancers including breast cancer.

Researchers from Texas MD Anderson Cancer Center discovered that, loss of α-catenin as a mechanism by which the NF-kB pathway is activated in the basal-like subtype of breast cancer. This is highly relevant in human tumors, as alpha-catenin is specifically downregulated in human basal-like breast cancer, correlates with recurrence-free survival and negatively correlates with the activity of NF-κB signalling. Thus, Targeting the NF-κB pathway may provide therapeutic benefits to patients with basal-like, triple-negative breast cancer

 Reference: alpha-catenin acts as a tumour suppressor in E-cadherin-negative basal-like breast cancer by inhibiting NF-κB signalling. Nature cell biology, 2014

Microbes and Colon Cancer

The human large bowel is a common site for adenocarcinomas and also one of the most densely populated microbial ecosystems on our planet. Colorectal cancers affect over a quarter of a million people each year. When the disease is local or confined, cure rates range from 70%–90%; however, advanced colorectal cancers has a high mortality rate, consistently ranking in the top three causes of cancer-related death around the globe. There has been long-standing curiosity about the role of bacteria in colorectal carcinogenesis.

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Colorectal cancers is essentially a genetic disease,the following graph is showed genetic alterations and the progression of colorectal cancers.

Some models support the hypothesis that the microbe contributes to colon carcinogenesis. Such as, Streptococcus gallolyticus, Enterococcus faecalis, Enterotoxigenic Bacteroides fragilis, Escherichia coli and Fusobacterium spp. Specific microbes, a microbial community, or the two acting sequentially and/or in synergy are three models.

Cancer has been called the ‘‘emperor of all maladies’’, and in unraveling the role of the microbiota in colorectal carcinogenesis, research efforts are giving this emperor new clothes and laying him bare. With sufficient research support, the vast genomic and metabolic potential of the gut microbiota may be realized as the most powerful weapon in the 40-plus year war on cancer. Specific species, microbial consortia, and microbial metabolites generated from ingested foodstuffs are all potential targets for decreasing or increasing cancer risk and perhaps even for diagnosis, treatment stratification, and therapy.

Reference: Cynthia L. Sears and Wendy S. Garrett, Cell Host & Microbe, 2014

Marian R.Glancy

Cancer related signaling pathway, e.g. Wnt signaling,stat3,NF-KB