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.

 (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

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.

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

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

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.

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.

 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.