Using various ARKO mouse models to study AR roles in various tumors

The androgen receptor (AR) is expressed in many cell types and the androgen/AR signaling has been found to have important roles in modulating tumorigenesis and metastasis in several cancers including prostate, bladder, kidney, lung, breast and liver. However, whether AR has differential roles in the individual cells within these tumors that contain a variety of cell types remains unclear. Generation of AR knockout (ARKO) mouse models with deletion of AR in selective cells within tumors indeed have uncovered many unique AR roles in the individual cell types during cancer development and progression.

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A recent review published in “Oncogene” discussed the results obtained from various ARKO mice and different human cell lines with special attention to the cell type- and tissue-specific ARKO models. The understanding of various results showing the AR indeed has distinct and contrasting roles in each cell type within many hormone-related tumors (as stimulator in bladder, kidney and lung metastases vs as suppressor in prostate and liver metastases) may eventually help us to develop better therapeutic approaches by targeting the AR or its downstream signaling in individual cell types to better battle these hormone-related tumors in different stages.

Reference:

Androgen receptor (AR) differential roles in hormone-related tumors including prostate, bladder, kidney, lung, breast and liver. Oncogen. 2014;33:3225-3234

PI3K in cancer–stroma interactions

The phosphoinositide-3 kinase (PI3K) signaling pathway is one of the most frequently deregulated signaling cascades in tumor initiation and progression. PI3K enzymes are crucial effectors of a broad range of extracellular stimuli and mediate activation of signal transduction events regulating cell survival, morphology and migration of malignant and non-malignant cells.

Over the past decade the phosphoinositide-3 kinase (PI3K) signaling pathway emerged as an important player for tumor initiation and growth and, currently, PI3K inhibition constitutes a promising therapeutic approach for solid and hematological tumors. Beside its role in tumor cell evolution, PI3K signaling also provides integral functions for noncancerous cells that reside in healthy tissues surrounding the tumor, also referred as tumor microenvironment (TME). This review will address how PI3K signaling participates to the tumorigenic process and discuss the interaction between tumor cells and the surrounding TME, with particular focus on the role of PI3Ks in tumor-associated immune responses, tumor angiogenesis and metastasis formation.

PI3K signaling and tumor-associated immune response

Immune cells and mediators are fundamental components of TME. Depending on the cell type involved, the immune response can have either pro- or anti-tumorigenic functions. Notably, cytotoxic T lymphocytes, T helper and NK cells are able to recognize and destroy tumor cells as well as circulating tumor metastases, a process known as immune surveillance. Their presence in the TME is thus largely recognized as a factor of good prognosis. Conversely, cells normally involved in chronic inflammation, such as monocytes, granulocytes and mast cells, provide the tumor with growth factors, angiogenic factors and enzymes for extracellular matrix (ECM) remodeling, which favor tumor progression and relapse.

PI3K signaling in tumor angiogenesis

The ability of tumors to grow and invade strictly relies on the formation of new blood vessels that provide the adequate supply of nutrients and oxygen. Tumor neovascularization is coordinated by a plethora of cell types that either reside in or are recruited to TME. Tumor cells provide the first cue for neoangiogenesis, as they secrete pro-angiogenic factors, such as the vascular endothelial growth factor (VEGF), that activate naturally quiescent endothelial cells. New blood vessels thereby originate from pre-existing vascular structures as a result of intensive proliferation and migration of activated endothelial cells. In addition, tumor infiltrating bone marrow-derived cells, including monocytes, mast cells and endothelial progenitor cells, can directly promote angiogenesis and vasculogenesis.

PI3K signaling in ECM remodeling

Cellular components of the TME are immersed in the ECM, a complex network of macromolecules that is intensively modified and remodeled during cancer progression. Pathogenic remodeling of ECM in the TME is mainly due to CAFs, that secrete ECM components and ECM-modifying enzymes. CAFs appear to constitute a heterogeneous population of cells and their origin is still debated. The most widely accepted view is that CAFs are early developmental precursors that respond to signals derived from cancer cells. Among these signals, some are PI3K-mediated, such as the hepatocyte growth factor, the epidermal growth factor (EGF) and the basic fibroblast growth factor. It is thus conceivable that PI3K inhibition may prevent CAFs expansion and consequent setting of a tumor-supporting ECM.

PI3K signaling in metastasis

Tumor inflammation, neo-angiogenesis and matrix remodeling are interconnected processes that eventually contribute to the end-stage of tumorigenesis represented by tumor dissemination. Beside intense TME remodeling, metastasis is a multi-stage process involving cancer cell motility out of the primary tumor, intravasation into the circulatory system, transit in the blood or lymph, extravasation and proliferation at a new distant site. In cancers of epithelial origin, these processes are favored by epithelial-to-mesenchymal transition (EMT), a developmental regulatory program that relinquishes tumor cells from intrinsic polarization and adhesion to the ECM, eventually facilitating the rise of satellite lesions. EMT is coordinated by a set of pleiotropically acting transcriptional factors, such as Snail, Slug, Twist and Zeb1/2.

PI3K inhibitors: attack on multiple fronts

The various roles of PI3K-mediated signaling in the cross-talk between the tumor and its microenvironment clearly indicate a therapeutic potential. However, the identification of strategies aimed at blocking oncogenic PI3K signaling without affecting important systemic functions is still a challenge. Inhibition of all PI3Ks causes a potent blockade of the pathway and thus appears attractive, as it can concomitantly hit the tumor in its weak points. However, systemic toxicity of pan-PI3K inhibitors represents a major drawback. As different PI3K isoforms have different expression patterns and activation mechanisms, inhibition of specific PI3K isoforms in defined tumors appears a way to circumvent toxicity issues.

Make Breast Cancer at Bay with Evolving Therapies

When it comes to a topic that individualized medicine walks into a reality, scientists would stress that the current challenge is identifying different subtypes of patients so that treatment can be truly tailored to the individual.

Clinical developments have enabled the classification of patients into various subtypes, based on anatomical and pathological findings. Currently, samples from cancer patients are routinely tested for relevant biomarkers in order to tailor the treatment. The ultimate goal is to get the right drug to the right patient, at the right time.

Genetic testing in breast cancer is becoming common practice to predict each patient’s therapeutic effect and risk of recurrence. Testing for ER positivity enables physicians to determine the likelihood of response to endocrine therapy and provides a variety of treatment options. HER2 presents in around 25% of cases, and is associated with an aggressive form of the disease. The monoclonal antibody trastuzumab targets HER2 and is active in patients expressing this receptor.

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“Treatment today is getting much more individualized,” says Dr. Clifford A. Hudis, chief of breast cancer medicine service at Memorial Sloan Kettering Cancer Center in New York. “Depending on the molecular nature of a woman’s tumor, postoperative hormonal treatment or other drug treatments are routinely prescribed to prevent or delay a recurrence of disease.”

Cancer therapy and its environment

Gone is the simplistic notion that cancer is a disease of abnormal cell division, said Dr. Larry Norton, deputy physician-in-chief for breast cancer programs.”It’s a disease of abnormal relationships between the cancer cell and other cells in its environment.”

This new perspective is leading to changes in treatment. Bevacizumab, as the first FDA-approved angiogenesis Inhibitor, slows or blocks the formation of blood vessel to treat cancer. It is based on the discovery that tumour sends out signals to nearly blood vessel causing new capillaries to sprout towards the tumour, thereby effectively hijacking the blood supply. Therefore, this monoclonal antibody blocks cancer cell growth by cutting off supplies from its environment.

In light of this new perspective, current surgery for breast cancer involves removing only a few lymph nodes, rather than a whole, for testing. “We know that in many cases we’re leaving behind nodes that contain cancer cells, but it doesn’t hurt the patient to leave them there. Because cancer cells require other cells in their vicinity to help them grow, it’s not true that if there’s one cancer cell left it will definitely grow and cause trouble.”Dr. Norton said.

Cancer immunotherapy

Instead of waiting for cancer to recur in certain high-risk patients, scientists are now developing techniques to outwit the cancer cell’s aggressive tactics by recruiting the patient’s immune system to launch a continuous attack.

Knowing that the effectiveness of treatment is reduced once cancer has metastasized, researchers are now testing creative ways to prevent such recurrences. One, a specially designed vaccine called NeuVax, is in the final stage of multinational clinical tests.

The vaccine is made from a peptide, a small piece of a cancer protein, that is combined with an immune stimulant. Early results suggest that the vaccine can reduce the risk of recurrence by 50 percent among breast cancer patients whose tumors produce low levels of the protein HER2, a marker for more aggressive breast cancer.

Another approach under study involves destroying the tumor by freezing it with an ice probe, but leaving it in place so that the immune system can be trained to attack it, Dr. Hudis said. The patient then would be given an immune stimulant to help overcome the molecular obstacles that had kept the immune system from recognizing the cancer as foreign tissue.

References:

1. The HER2 peptide nelipepimut-S (E75) vaccine (NeuVax™) in breast cancer patients at risk for recurrence: correlation of immunologic data with clinical response. Immunotherapy. 2014 May;6(5):519-31.

2. Phase II study of weekly intravenous trastuzumab (Herceptin) in patients with HER2/neu-overexpressing metastatic breast cancer. Semin Oncol. 1999 Aug;26(4 Suppl 12):78-83

Long Telomere Leads to Health or Brain Cancer?

When I hear that some gene, or protein has the potential to prolong our life, I am doubled very much. Our bodies wear out and any effort to reverse this biological process risks turning up cancer. As the telomere caps on chromosome ends wear down, Cells would lose the ability to divide. So longer telomere caps good? Shorter telomere caps bad? It’s not that easy.

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A new research conducted by UC San Francisco (UCSF) scientists reveals that 2 common gene variants link to long telomeres, the caps on chromosome generally thought to be a sign of slow biological ageing, also raise the risk of deadly brain cancers known as gliomas.

Identify “culprit” gene

In this research, researchers analyzed genome-wide data from 1,644 glioma patients and 7,736 healthy control individuals, including some who took part in The Cancer Genome Atlas project sponsored by the National Cancer Institute and National Human Genome Research Institute. This work identify risk alleles for glioma near TERC and TERT that also associate with telomere length.

The genetic variants, in the TERT and TERC genes known to regulate the action of telomerase, are respectively carried by 51% and 72% of the population. Because it is somewhat unusual for such risk-conferring variants to be carried by a majority of people, the researchers propose that in these carriers the overall cellular robustness afforded by longer telomeres trumps the increased risk of high-grade gliomas, which are invariably fatal but relatively rare cancers.

“Though longer telomeres might be good for you as a whole person, reducing many health risks and slowing aging, they might also cause some cells to live longer than they’re supposed to, which is one of the hallmarks of cancer,” said lead author Kyle M. Walsh, PhD, assistant professor of neurological surgery and a member of the Program in Cancer Genetics at UCSF’s Helen Diller Family Comprehensive Cancer Center.

Previous Research on telomere 

UCSF’s Elizabeth Blackburn, PhD, shared the 2009 Nobel Prize in Physiology or Medicine for her pioneering work on telomeres and telomerase, an area of research she began in the mid-1970s. In the ensuing decades, untangling the relationships between telomere length and disease has proved to be complex.

In much research, longer telomeres have been considered a sign of health — for example, Blackburn and others have shown that individuals exposed to chronic stressful experiences have shortened telomeres. But because cancer cells promote their own longevity by maintaining telomere length, drug companies have searched for drugs to specifically target and block telomerase in tumors in the hopes that cancer cells will accumulate genetic damage and die.

In some of these cases, the disease-associated variants promote longer telomeres, and in others shorter telomeres, suggesting that “both longer and shorter telomere length may be pathogenic, depending on the disease under consideration,” the authors write.

References:

1. Variants near TERT and TERC influencing telomere length are associated with high-grade glioma risk. Nature Genetics on June 8, 2014

2. Telomeres and telomerase: their mechanisms of action and the effects of altering their functions. FEBS Lett. 2005 Feb 7;579(4):859-62.

Insight into Cancer Predisposition Genes

Genes, in which key mutations confer highly or moderately increased risks of cancer, are called cancer predisposition genes. A finding by Dr. Nazneen Rahman in the Institute of Cancer Research shows that over 100 of cancer predisposition genes identified provide important scientific insights in many areas ,particularly the mechanism of cancer causation.

Furthermore, changes in predisposition genes, each with a small effect, may underlie susceptibility to cancer. Thus, clinical use of these genes can make a substantial effect on diagnosis, prevention, and treatment of cancer. The recent advances in the next-generation sequencing hold the promise of discovering many more cancer predisposition genes.

Currently, scientists mainly work on identifying genetic variants that have a small impact on cancer risk but are common in the general population. Although each of these variations only act slightly, mutation accumulation of different genes may increase the risk of suffering cancer significantly according to multiple “hits” theory of carcinogenesis.

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Genetic disposition to breast cancer

Genetic variations make an important contribution in developing breast cancer. For instance, certain mutations in the BRCA1 or BRCA2 genes greatly increase a person’s risk of developing breast cancer, identified by genome-wide linkage analysis and positional cloning. Mutational screening of genes functionally related to BRCA1 and/or BRCA2 has revealed four genes, CHEK2, ATM, BRIP1, and PALB2; mutations in these genes are rare and confer an intermediate risk of breast cancer.

Additionally, Variations in other genes, such as BARD1 and BRIP1, also increase breast cancer risk, but the contribution of these genetic changes to a person’s overall risk appears to be much smaller. Despite these discoveries, most of the familial risk of breast cancer remains unexplained.

Genetic disposition to colorectal cancer

Genetic variations can affect the risk of developing colorectal cancer. The 2 major types of genomic instability found in colorectal cancers are chromosomal instability (CIN) and microsatellite instability (MSI). CIN is often associated with mutated APC. The associated familial cancer susceptibility syndromes are familial adenomatous polyposis coli, due to inherited APC mutations, and Lynch Syndrome or hereditary nonpolyposis colorectal cancer syndrome, due to inherited mutations in one of the mismatch repair genes (predominantly MLH1 and MSH2)

A large number of genetic tests are available to judge whether a person has a genetic variant that predisposes him or her to colorectal cancer, including APC, MLH1, and MSH2 mutations.

Genetic disposition to gastric cancer

The association of gastric polyps and cancers in familial adenomatous polyposis(FAP) implicates the APC gene in gastric carcinogenesis. Inactivation of the APC gene on chromosome 5q is seen in about 20% of early sporadic gastric cancers, but is predominately associated with the differentiated diffuse disease. The APC gene therefore appears to play a key role in initiation of a subset of sporadic gastric as well as colonic cancers.

Possible sites of other predisposition genes, such as tumour suppressor genes, can be identified from sites of chromosomal loss. These can be detected either cytogenetically or by loss of heterozygosity (LOH) using microsatellite markers. LOH at chromosomes 1p, 5q, 7q, 11p, 13q, 17p and 18p among others has been observed in a high percentage of gastric cancers.

Although cancer predisposition genes can be employed for clinical practice guidelines, there is also high potential for incorrect inferences and inappropriate clinical applications. Thus realizing the promise of cancer predisposition genes for science and medicine will thus require careful navigation.

References:

1.  Realizing the promise of cancer predisposition genes. Nature. 2014 Jan 16;505(7483):302-8.

2.  Common breast cancer-predisposition alleles are associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers. Am J Hum Genet. 2008 Apr;82(4):937-48

3.  Abnormalities affecting the APC and MCC tumour suppressor gene loci on chromosome 5q occur frequently in gastric cancer but not in pancreatic cancer. Int J Cancer 1993; 55:598–603.

4. Pathways of colorectal carcinogenesis. Appl Immunohistochem Mol Morphol. 2013 Mar;21(2):97-102.

Expression of androgen receptor in inflammatory breast cancer may have therapeutic significance

Inflammatory breast cancer (IBC) is a rare and very aggressive disease with characteristic symptoms that include redness, swelling, tenderness, and warmth in the breast because of dermal lymphatic occlusion by tumor emboli. Despite multimodality treatment approaches, the prognosis of patients with IBC remains poor, with a clinical outcome much worse than that of patients with non-inflammatory breast cancer. Identifying novel therapeutic targets is highly desirable.

Emerging evidence is indicating that the androgen-signaling pathway plays a role in breast carcinogenesis through regulating estrogen-responsive genes. Androgen receptor (AR) expression in breast cancer has become an interesting topic of research, because AR can be targeted by anti-androgen agents such as bicalutamide and enzalutamide, which have been widely used to treat patients with AR-positive, advanced prostate cancers. Similar to estrogen receptor (ER) and progesterone receptor (PR), AR is a member of the steroid hormone receptor family. Depending on the study population, testing method, and cutoff values used, AR reportedly is expressed in 70% to 90% of invasive breast cancers.

A significant association between AR and ER expression has been reported in breast carcinoma, not otherwise specified (NOS).Peters et al observed coexpression of the 2 receptors in 80% to 90% of breast tumor cells.AR positivity also reportedly is associated with older age and/or postmenopausal status at diagnosis, smaller tumor size, lower tumor grade, negative human epidermal growth factor receptor 2 (HER2) status, and negative lymph node metastasis. However, AR positivity is also reported in 30% to 50% of ER-negative/PR-negative and triple-negative tumors.

To date, the prevalence of AR expression in IBC tumors and its association with survival in patients with IBC have not been evaluated. The objectives of the current study were to examine the prevalence of AR expression in IBC tumors and to explore its prognostic value. Yun Gong published a study included 88 patients with primary IBC who were treated at The University of Texas MD Anderson Cancer Center from September 1994 to August 2004 and for whom tumor tissue and clinical follow-up information were available. The diagnosis, preoperative and postoperative treatments of these patients, biomarker study (encompassing ER, PR, and HER2 status), and tissue microarray (TMA) construction have been previously reported.Notably, ER, PR, and HER2 status and tumor characteristics were evaluated on pretreated tumor samples obtained by core-needle biopsy, and a TMA was built up using postneoadjuvant residual tumors. This study was approved by the Institutional Review Board.

In this study, the median follow-up was 10.8 years (range, 0.7-14.5 years), and the 5-year OS and DSS rate were 46% and 49%, respectively. AR was positive in 39% of IBC tumors overall, and in 33.3% of ER-negative tumors, 29.3% of PR-negative tumors, and 42.6% of triple-negative tumors. Positive AR expression was significantly associated with lymphovascular invasion (P = .01). However, there was no significant association between AR positivity and ER, PR, or HER2 status or other pathologic parameters , but there was a trend toward an association between AR and PR expression (P = .07)

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The study demonstrated that AR is commonly expressed in post-treated IBC tumors. AR positivity was significantly associated with lymphovascular invasion, and there was a trend toward an association between AR expression and PR expression. Patients who had IBC with AR-negative/ER-negative tumors had significantly worse OS and DSS than patients who had tumors that exhibited other combinations of AR/ER status. For patients with AR-positive IBC tumors, an AR-modulated therapeutic approach may add to the existing treatment to improve patients’ outcomes. Further study with a larger series will be required to delineate the biologic mechanisms of AR and their clinical significance in IBC tumors.

Reference:

Expression of androgen receptor in inflammatory breast cancer and its clinical relevance. Cancer.2014;120:1775-1779

Hypermethylation of the ABCB1 downstream gene promoter in docetaxel-resistant MCF-7 breast tumor cells

One of the largest problems in the treatment of breast cancer is the development of multidrug resistance (MDR), where tumor cells possess or acquire the ability to circumvent the killing action of a variety of structurally unrelated chemotherapy drugs.  The MDR mechanisms involve increased drug efflux from tumor cells due to induction of ATP-binding cassette (ABC) drug transporters. Higher expression of the ABCB1 drug transporter is often observed in drug-resistant tumor cells, although the precise mechanism remains unclear.

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Recently epigenetic alterations including changes in methylation of CpG islands within gene promoters have emerged as a prominent mechanism for regulation of gene expression. CpG island methylation may repress transcription via the downstream promoter, while histone acetylation may play an important role in upstream promoter activation.

Through bisulfite sequencing experiments we found that the ABCB1 downstream promoter became increasingly methylated following the acquisition of drug resistance. This hypermethylation in turn correlated with increased ABCB1 gene amplification, a switch from usage of the ABCB1 downstream promoter to the upstream promoter, increased ABCB1 expression, and increased drug resistance. The cytotoxic activity of docetaxel is exerted by promoting and stabilising microtubule assembly, while preventing physiological microtubule disassembly in the absence of GTP.

This study is the first to examine broad-scale changes in ABCB1 gene methylation associated with the acquisition of docetaxel resistance and the first report of ABCB1 transcription exclusively via the upstream promoter.

Dysregulation of target genes of SOX2 is very likely to contribute to tumorigenesis or cancer progression

Lung cancer is the leading cause of cancer-related death in many countries in the world. Among all subtypes of lung cancer, non-small cell lung carcinoma (NSCLC) is the most frequent one, which accounts for greater than 80% of lung cancers.The prognosis of NSCLC patients is poor, with the 5-year survival rate of only about 18%, and the high mortality of NSCLC is thought to be attributed to difficulties in early diagnosis and the lack of effective therapeutic methods in general. NSCLC can be further classified into three histological subtypes, i.e., squamous cell carcinoma (SQC), adenocarcinoma (ADC) and large cell carcinoma (LCC). Among these subtypes, SQC and ADC are the major ones, which together represent ∼70% of NSCLC. SQC was once the most common subtype of NSCLC during the past century. However, it was noted later that proportion of SQC relative to ADC declined gradually, most probably owing to change in smoking behavior and improved diagnostic methods. Today, ADC is the most common subtype in many countries, while SQC is estimated to account for 20–25% of NSCLCs.

Compared with ADC of the lung, in which many driver mutations have been identified and targeted therapies are applicable to a good proportion of patients especially in the Far Eastern countries, neoplasms of SQC of the lung were once regarded as tumors without readily targetable genetic abnormalities. However, recent studies have identified new lung SQC-associated genetic changes, including the amplification and overexpression of SOX2. SOX2 is located on chromosome 3q26, a region amplified in about 20% of lung SQC. At a much higher rate than gene amplification, overexpression of SOX2 mRNA was observed in about 90% of the lung SQC, indicating that SOX2 might play oncogenic role(s) in the tumorigenesis of lung SQC, which is supported by studies reporting that SOX2 is a lineage-survival oncogene of SQC of the lung.

As SOX2 functions upstream of the hierarchy of gene expression network, it is likely that its aberrant expression in lung epithelia could cause profound change in a wide variety of molecular pathways, which may contribute to growth and survival of the lung SQC cells. Although the oncogenic role of SOX2 in lung SQC has been identified, there is still a paucity in the understanding of the mechanisms regarding how SOX2-mediated signaling network affects the formation or progression of lung SQC cells.

In an initiative, using SOX2-abundant lung SQC cell lines, Wen-Tsen Fang et al. screened for genes whose expression was not only affected by silencing of SOX2 but can also account for the inhibition of cell growth upon SOX2 silencing. Among the other candidate genes, they found that BMP4, a member of the TGF-β superfamily genes, was significantly affected by silencing SOX2. As genes of TGF-β family are well known for their involvement in the regulation of cell proliferation and differentiation, they postulated that BMP4 is a plausible target of SOX2. In their study, several lines of evidence from in vitro and in vivo observation were provided showing that BMP4 expression may be transcriptionally suppressed by SOX2 to promote growth of lung SQC cells.

Reference:

Downregulation of a putative tumor suppressor BMP4 by SOX2 promotes growth of lung squamous cell carcinoma. Cancer Cell Biology.2014;135:809-819

Combine immune response with radiation therapy

Radiation therapy is used in the treatment of around 50% of cancer patients and remains the most important nonsurgical treatment in the management of solid malignancies. Treatment with ionizing radiation (IR) induces lethal DNA damage leading to cellular death through mitotic catastrophe, necrosis and apoptosis. Recent evidence also suggests that treatment with IR can render the tumor cells immunogenic and potentially generate antitumor immune responses.

Exposure of cancer cells to IR leads to cellular stress and the expression of several damage-associated molecular patterns (DAMPs). These include High Mobility Group Box 1 (HMGB1) and the extracellular release of ATP, which can activate professional antigen presenting cells (APCs), such as the dendritic cell (DC), and engender tumor antigen-specific T-cell responses. In addition, the induction of DNA damage subsequent to treatment with IR can lead to the production of novel (and potentially immunogenic) proteins and has been shown to upregulate tumor cell expression of class I MHC. Taken together, these data demonstrate the immunogenic potential of radiation therapy for cancer. Data from preclinical studies, however, demonstrate that established tumors foster immunosuppressive microenvironments that favor angiogenesis and the production of cytokines such as transforming growth factor-β (TGF-β) and interleukin-10 (IL-10), which attenuate TH−1 cytotoxic activity. Consequently, in both preclinical and clinical studies the use of IR alone is rarely capable of generating durable tumor antigen-specific immune responses. However, several preclinical studies have demonstrated the generation of systemic immune responses following combination therapy with IR and immuno-modulators such as monoclonal antibodies to CTLA4 and CD40, and small molecule agonists of the Toll-like receptor (TLR) family members TLR7 and TLR9.

Members of the TLR family are responsible for recognizing a diverse array of evolutionarily conserved pathogen-associated molecular patterns and are constitutively expressed by both professional APCs and effector immune cell populations. Activation of TLR7, which is localized intracellularly in endosomal membranes and recognizes viral guanosine and/or uridine-rich single-stranded RNA, leads to a MyD88-dependent signaling cascade ultimately resulting in interferon regulatory factor-7 (IRF-7), AP-1 or NFκB-mediated transcription of TH1 cytokines, predominantly Type I interferon (IFN).

Synthetic small molecule agonists of TLR7 have been developed such as imiquimod (Aldara 5% cream, 3M), which is FDA-approved for the treatment of genital warts and superficial basal cell carcinoma. However, delivery of topical TLR7 agonists to noncutaneous tumors is challenging and would require image-guided delivery such as ultrasound or computerized tomography. We have previously demonstrated that systemic delivery of a TLR7-selective small molecule agonist leads to the priming of systemic immune responses capable of reducing both primary and metastatic tumor burden. The TLR7 agonist 852A (Pfizer) is currently one of the most extensively studied compounds to be tested systemically in clinical trials. Amy L. Adlard et al. assessed the antitumor efficacy of a newly described systemically administered 8-oxoadenine derivative, DSR-6434, which has a higher water solubility and a 300-fold greater potency for human TLR7 than 852A. Their results demonstrate that systemic administration of DSR-6434 can enhance the effectiveness of radiotherapy in two syngeneic tumor models and that this occurs as a consequence of TLR7 activation and the generation of tumor-specific immune responses.

Reference:

A novel systemically administered toll-like receptor 7 agonist potentiates the effect of ionizing radiation in murine solid tumor models. Tumor Immunology . 2014;135:820-829

Therapeutic Combination: The Blockage of Cancer Signaling Pathways

When cancer patients are initially diagnosed, they eagerly wonder if it’s curable. That’s because pharmacists and doctors are engaging in the development of novel treatment regimens that are expected to be more effective than traditional chemotherapies, and have fewer side effects. Indeed, they’re finding that therapeutic combinations have the potential to be more effective in slowing or even blocking cancer growth.

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Biologic agents act against oncogenic proteins or enzymes in tumor cells that drive cancer development. However, considering complex signaling networks, including these proteins, interact through crosstalk and feedback loops to form drug resistance , clinical physicians would envision several trial designs to achieve the optimal drug combination.

“Cell signals operate in pathways, or networks, similar to interstate highways. When the interstate is clear, traffic runs smoothly. But an accident at one part, or a closed exit ramp, can lead to massive traffic snarls. That’s what happens in cancer, where an error in any signal along the pathway can bring the entire growth-regulating system to a halt.” explains Lebwohl, senior vice president and global head of Oncology Clinical Development at Novartis.

Biomarkers and therapeutic combination

Nearly all pharmaceutical companies are investigating oncogenic proteins, or biomarkers, which initiate the development of potential drugs. For instance, currently most of Roche’s anti-cancer drug candidates in clinical development are being developed with targeted biomarkers, by which doctors can distinguish the certain patients with potential pharmaceutical benefit.

Biomarker studies can help to understand disease biology and to identify patient subgroups in favour of genotyping. Moreover, biomarkers can help to understand the outcome of therapeutic combination and how to rationally design therapeutic combination. Finally, another goal of biomarker research is to understand the development of resistance against cancer therapies and overcome this issue.

A successful therapeutic Combination against cancer

A new study, published in the Lancet oncology, firstly demonstrate chemotherapy and a targeted therapy in combination work better than chemotherapy alone in treating lung cancer patients with KRAS mutation.

The 87 patients who participated in the phase II trial had advanced, KRAS-mutant NSCLC that had failed initial chemotherapy. They were randomly assigned to receive either selumetinib and the chemotherapy agent docetaxel or docetaxel alone. As investigators found, patients receiving selumetinib lived a median of 5.3 months before their cancer began to worsen, compared to 2.1 months for those receiving chemotherapy alone.

“Our findings suggest that selumetinib and docetaxel work synergistically – each enhancing the effect of the other,” says Dr. Pasi A. Jänne, HMS associate professor of medicine at Dana-Farber Cancer Institute. “This opens the possibility that there may finally be a therapeutic strategy using a targeted therapy which could be clinically effective in this population of KRAS-mutant lung cancer patients.”

References:

1.  Development of therapeutic combinations targeting major cancer signaling pathways. J Clin Oncol. 2013;31(12):1592-605.

2. Selumetinib plus docetaxel for KRAS-mutant advanced non-small-cell lung cancer: a randomised, multicentre, placebo-controlled, phase 2 study. Lancet Oncol. 2013;14(1):38-47.