Dietary selenium fails to influence cigarette smoke-induced lung tumorigenesis in A/J mice.

Higher dietary sodium selenite did not inhibit the induction of lung tumors. • Higher dietary selenium increased selenium and GPx protein levels in the lung. • Dietary selenium did not affect lung SOD levels.

Abstract

The goal of the study was to determine if dietary selenium inhibited the induction of lung tumorigenesis by cigarette smoke in A/J mice. Purified diets containing 0.15, 0.5, or 2.0mg/kg selenium in the form of sodium selenite were fed to female A/J mice. Half of the mice in each dietary group were exposed to cigarette smoke 6h/day, 5days/week for five months followed by a four month recovery period in ambient air, while the other half were used as controls. After the recovery period, the mice were euthanized, and their lungs were removed for further analysis. Mice exposed to smoke had a higher tumor incidence and a higher tumor multiplicity, whereas dietary Se did not affect either the tumor incidence or tumor multiplicity. An increase in dietary selenium led to increased levels of selenium in the lung as well as GPx protein levels, but dietary Se did not affect lung SOD protein levels. In conclusion, these data confirm the carcinogenic activity of cigarette smoke in mice but show that dietary Se provided as sodium selenite does not affect smoke-induced carcinogenesis in this model.

Source: cancer letters

 

 

 

 

 

Dual-therapeutic reporter genes fusion for enhanced cancer gene therapy and imaging.

Two of the successful gene-directed enzyme prodrug therapies include herpes simplex virus–thymidine kinase (HSV1–TK) enzyme-ganciclovir prodrug and the Escherichia coli nitroreductase (NTR) enzyme-CB1954 prodrug strategies; these enzyme-prodrug combinations produce activated cytotoxic metabolites of the prodrugs capable of tumor cell death by inhibiting DNA synthesis and killing quiescent cells, respectively. Both these strategies also affect significant bystander cell killing of neighboring tumor cells that do not express these enzymes. We have developed a dual-combination gene strategy, where we identified HSV1-TK and NTR fused in a particular orientation can effectively kill tumor cells when the tumor cells are treated with a fusion HSV1-TK–NTR gene– along with a prodrug combination of GCV and CB1954. In order to determine whether the dual-system demonstrate superior therapeutic efficacy than either HSV1-TK or NTR systems alone, we conducted both in vitro and in vivo tumor xenograft studies using triple negative SUM159 breast cancer cells, by evaluating the efficacy of cell death by apoptosis and necrosis upon treatment with the dual HSV1-TK genes-GCV-CB1954 prodrugs system, and compared the efficiency to HSV1-TK–GCV and NTR-CB1954. Our cell-based studies, tumor regression studies in xenograft mice, histological analyses of treated tumors and bystander studies indicate that the dual HSV1-TK–NTR–prodrug system is two times more efficient even with half the doses of both prodrugs than the respective single gene-prodrug system, as evidenced by enhanced apoptosis and necrosis of tumor cells in vitro in culture and xenograft of tumor tissues in animals.

Source:Nature

 

 

 

Protein phosphatase 2A: a target for anticancer therapy.

Protein phosphatase 2A (PP2A), one of the main serine—threonine phosphatases in mammalian cells, maintains cell homoeostasis by counteracting most of the kinase-driven intracellular signalling pathways. Unrestrained activation of oncogenic kinases together with inhibition of tumour suppressors is often required for development of cancer. PP2A has been shown to be genetically altered or functionally inactivated in many solid cancers and leukaemias, and is therefore a tumour suppressor. For example, the phosphatase activity of PP2A is suppressed in chronic myeloid leukaemia and other malignancies characterised by aberrant activity of oncogenic kinases. Preclinical studies show that pharmacological restoration of PP2A tumour-suppressor activity by PP2A-activating drugs (eg, FTY720) effectively antagonises cancer development and progression. Here, we discuss PP2A as a druggable tumour suppressor in view of the possible introduction of PP2A-activating drugs into anticancer therapeutic protocols.

Source: lancet

 

Genomic Studies Allow Better Classification of Leukemias, Endometrial Tumors.

Two studies, one of leukemia and the other of endometrial tumors, show the usefulness of genomics studies in finding unsuspected classifications, possibly useful for treating these cancers.

One study, published in the New England Journal of Medicine, examined 200 cases of acute myeloid leukemia. Genomic studies allowed the researchers to discern nine distinct categories, revealing “many potentially important biologic relationships.” For instance, certain mutations were associated with distinct patterns of RNA activity. The authors point out that the significance of such findings “is not yet clear.”

Another study, in Nature, of some 375 endometrial cancers found four distinct classes of the disease, as opposed to the two commonly used to stage treatment. In Journal Watch Oncology and Hematology, Virginia Kaklamani observes that breast cancer was the first to use molecular subtypes to guide treatment. The Nature study, she writes, is “a huge step toward applying this technique in other malignancies.”

Source:NEJM

New Syndrome of Paraganglioma and Somatostatinoma Associated With Polycythemia .

Abstract

Purpose The occurrence of ≥ two distinct types of tumors, one of them paraganglioma (PGL), is unusual in an individual patient, except in hereditary cancer syndromes.

Patients and Methods Four unrelated patients were investigated, with thorough clinical evaluation. Plasma and tissue catecholamines and metanephrines were measured by high-performance liquid chromatography. Anatomic and functional imaging were performed for tumor visualization. Germline and tumor tissue DNA were analyzed for hypoxia-inducible factor 2 alpha (HIF2A) mutations. The prolyl hydroxylation and stability of the mutant HIF2α protein, transcriptional activity of mutant HIF2A, and expression of hypoxia-related genes were also investigated. Immunohistochemical staining for HIF1/2α was performed on formalin-fixed, paraffin-embedded tumor tissue.

Results Patients were found to have polycythemia, multiple PGLs, and duodenal somatostatinomas by imaging or biochemistry with somatic gain-of-function HIF2Amutations. Each patient carried an identical unique mutation in both types of tumors but not in germline DNA. The HIF2A mutations in these patients were clustered adjacent to an oxygen-sensing proline residue, affecting HIF2α interaction with the prolyl hydroxylase domain 2–containing protein, decreasing the hydroxylation of HIF2α, and reducing HIF2α affinity for the von Hippel–Lindau protein and its degradation. An increase in the half-life of HIF2α was associated with upregulation of the hypoxia-related genes EPO, VEGFA, GLUT1, and END1 in tumors.

Conclusion Our findings indicate the existence of a new syndrome with multiple PGLs and somatostatinomas associated with polycythemia. This new syndrome results from somatic gain-of-function HIF2A mutations, which cause an upregulation of hypoxia-related genes, including EPO and genes important in cancer biology.

 

Source: JCO

 

A case-matched study of stereotactic radiosurgery for patients with multiple brain metastases: comparing treatment results for 1–4 vs ≥ 5 tumors.

Abstract

OBJECT

Although stereotactic radiosurgery (SRS) alone for patients with 4–5 or more tumors is not a standard treatment, a trend for patients with 5 or more tumors to undergo SRS alone is already apparent. The authors’ aim in the present study was to reappraise whether SRS results for ≥ 5 tumors differ from those for 1–4 tumors.

METHODS

This institutional review board–approved retrospective cohort study used the authors’ database of prospectively accumulated data that included 2553 consecutive patients who underwent SRS, not in combination with concurrent whole-brain radiotherapy, for brain metastases (METs) between 1998 and 2011. These 2553 patients were divided into 2 groups: 1553 with tumor numbers of 1–4 (Group A) and 1000 with ≥ 5 tumors (Group B). Because there was considerable bias in pre-SRS clinical factors between Groups A and B, a case-matched study was conducted. Ultimately, 1096 patients (548 each in Groups A and B) were selected. The standard Kaplan-Meier method was used to determine post-SRS survival and the post-SRS neurological death–free survival times. Competing risk analysis was applied to estimate cumulative incidences of local recurrence, repeat SRS for new lesions, neurological deterioration, and SRS-induced complications.

RESULTS

The post-SRS median survival time was significantly longer in the 548 Group A patients (7.9 months, 95% CI 7.0–8.9 months) than in the 548 Group B patients (7.0 months 95% [CI 6.2–7.8 months], HR 1.176 [95% CI 1.039–1.331], p = 0.01). However, incidences of neurological death were very similar: 10.6% in Group A and 8.2% in Group B (p = 0.21). There was no significant difference between the groups in neurological death–free survival intervals (HR 0.945, 95% CI 0.636–1.394, p = 0.77). Furthermore, competing risk analyses showed that there were no significant differences between the groups in cumulative incidences of local recurrence (HR 0.577, 95% CI 0.312–1.069, p = 0.08), repeat SRS (HR 1.133, 95% CI 0.910–1.409, p = 0.26), neurological deterioration (HR 1.868, 95% CI 0.608–1.240, p = 0.44), and major SRS-related complications (HR 1.105, 95% CI 0.490–2.496, p = 0.81).

In the authors’ cohort, age ≤ 65 years, female sex, a Karnofsky Performance Scale score ≥ 80%, cumulative tumor volume ≤ 10 cm³, controlled primary cancer, no extracerebral METs, and neurologically asymptomatic status were significant factors favoring longer survival equally in both groups.

CONCLUSIONS

This retrospective study suggests that increased tumor number is an unfavorable factor for longer survival. However, the post-SRS median survival time difference, 0.9 months, between the two groups is not clinically meaningful. Furthermore, patients with 5 or more METs have noninferior results compared to patients with 1–4 tumors, in terms of neurological death, local recurrence, repeat SRS, maintenance of good neurological state, and SRS-related complications. A randomized controlled trial should be conducted to test this hypothesis.

Source: JNS

 

Circulating Tumor DNA Tracks Metastatic Breast Cancer in Proof-of-Concept Study.

A small study — deemed “more encouraging than definitive” by commentators — shows that circulating DNA from breast tumors can be used to track progression in metastatic breast cancer.

Researchers monitored the tumor burden of 30 women with metastatic disease with use of radiographic imaging plus assays of circulating tumor DNA, circulating tumor cells, and the cancer antigen CA 15-3.

Circulating tumor DNA was found in 29 of the 30 women with identifiable mutations. The sensitivity of the assays for CA 15-3 (78%) and circulating tumor cells (87%) was lower. Increasing levels of circulating DNA and tumor cells both correlated with inferior survival.

Writing in the New England Journal of Medicine, editorialists say the work “provides proof of the concept that circulating tumor DNA represents a sensitive biomarker of tumor burden” — and call for further studies.

Source: NEJM 

Beam of Hope.

 

Beth colorfully compares her first proton therapy treatment session to watching a scene from a science fiction movie unfold around her. Although the pristine white walls and state-of-the-art equipment conjure up images from the future, the technology will soon be a reality on the St. Jude Children’s Research Hospital campus. The hospital is currently building the world’s only proton center dedicated solely to the treatment of children.

Part of a $198 million project to enhance the hospital’s clinical and laboratory facilities, the St. Jude Red Frog Events Proton Therapy Center is slated to open in 2015.

The new center will greatly enhance the hospital’s ability to conduct research optimizing the use of proton therapy in children.

“This facility will enable us to complete important trials while providing the support that only St. Jude can provide to patients,” says Larry Kun, MD, chair of St. Jude Radiological Sciences.

What is proton therapy?

Proton therapy offers tremendous advantages compared to X-ray technology because it is more precise and may be used to deliver a potentially higher dose of radiation to the tumor with fewer side effects. By confining radiation exposure to the tumor itself, the pinpointed therapy reduces a person’s risk of experiencing toxic effects on major organs and of developing secondary cancers later in life.

“It’s exciting to hear that St. Jude is building its own proton therapy center,” adds Beth, who participated in a St. Jude protocol that involved traveling to Florida for treatment.

Beth was found to have a rare brain tumor known as craniopharyngioma when she was a college sophomore. After six weeks of daily proton therapy, which lasted from one to two hours each, Beth’s tumor is now smaller.

“St. Jude has given Beth hope, and that was more than any other therapy could offer,” says Beth’s mom.

Precise treatment

Beth’s doctor, Thomas Merchant, DO, PhD, division chief
of St. Jude Radiation Oncology, says proton therapy represents the next logical step for the hospital as it remains a world leader in the research and treatment of brain tumors and radiation therapy. Proton therapy can deliver high radiation doses directly to tumors while sparing normal tissues and reducing the side effects of traditional X-ray therapy. Proton therapy’s chief advantage is the ability to control its depth and intensity in tissue. The more precise the beam, the more targeted the therapy.

“It’s very important that we deliver precise treatment to children, and we’ve designed our facility in such a way that when it opens in 2015, it will have one of the narrowest beams in the United States,” says Merchant, who toured leading proton centers throughout the world in researching the project.

In addition to treating brain tumors, the new technology will also be used to treat Hodgkin lymphoma and other solid tumors such as Ewing sarcoma, neuroblastoma and retinoblastoma. Treatment sessions may range from 20 minutes to an hour.

“It’s been wonderful to be able to offer the treatment to our patients at the facility in Florida, but it’s a huge challenge for the families to have to uproot again,” says St. Jude social worker Melanie Russell. “When we have our own treatment facility here, it will be so much easier for our families.”

The new tower housing the facility will also include expanded surgical suites, an advanced Intensive Care Unit, the new Computational Biology department and a global education and collaboration center.

Source: http://www.stjude.org

The cancer stem cell discovery which sheds light on regrowth.

When different kinds of cancer are tackled, tumors may shrink in reaction to treatments including chemotherapy, but there is often the possibility of them springing back.

Some scientists believe that regrowth occurs because chemotherapy fails to eradicate a small number of cells, known in the field tentatively as ‘cancer stem cells’. It may be the case that these kinds of cells perform the same function in all cancers that create solid tumor masses.

The suspicion of stem cell cancer cells has long been an aspect of research in the field, but the hypothesis has remained controversial — mainly due to the artificial environments that most studies have taken place in, where human cells are transplanted into mice.

Now, studies on three different kinds of cancerous tumor has suggested a key reason why certain types of cells play a part in regrowth – stem cells that fuel the cancer and are not killed by standard therapies.

Published in the journals Nature and Science, the new studies conducted by three independent teams of researchers believe that this discovery may be a breakthrough in the field of cancer research.

Conducting tests on mice, so-called tumor stem cells were identified in the brain, skin and gut. In one case, researchers were able to prove that treating glioblastoma — a fatal brain tumor — with chemotherapy left behind these kinds of cells, and eventually this sparked regrowth.

Luis F. Parada, a molecular geneticist hailing from the University of Texas Southwestern Medical Center in Dallas, and author of one of the studies, said:

“Everything has a soft underbelly once you understand it well. With all the modern molecular techniques and modern approaches we have, we should be able to find their soft underbelly.”

Each study used color markers to detect when tumor cells divided in the mouse hosts. By doing so, the researchers were able to detect which cells did not replicate — and whether old cells can fuel regrowth, or it has to be stem cell subsets.

Robert Weinberg, a biology professor at MIT who was not involved in the new studies said:

“What these three papers have done, through elegant strategies, is demonstrate, indeed there are cancer stem cells. It makes it more and more difficult for people to doubt the existence of cancer stem cells.”

Source: Smart planet

 

 

Preventing Thrombosis During Chemotherapy.

Prophylactic anticoagulation with the low-molecular-weight heparin semuloparin reduced the incidence of thromboembolic events without increasing the risk for major bleeding.

Venous thromboembolism (VTE) often complicates cancer and is related to patient performance status, tumor stage, and treatment. Many chemotherapeutic agents increase the risk for VTE, even in ambulatory outpatients. However, whether prophylactic anticoagulation diminishes VTE risk during chemotherapy is unclear.

To address this issue, an international team of investigators conducted an industry-supported, randomized, double-blind, placebo-controlled trial involving 3212 patients who were beginning to receive chemotherapy for cancers typically associated with an increased risk for VTE; 36% of patients had lung cancer, and 28.9% had colorectal cancer. Most tumors (66%) were metastatic; the remaining tumors were locally advanced. Patients with adequate renal function (creatinine clearance >30 mL/minute) received either the hemisynthetic low-molecular-weight heparin (LMWH) semuloparin (20 mg/day subcutaneously) or placebo for a median 3.5 months.

The primary outcome — any symptomatic deep venous thrombosis (DVT), nonfatal pulmonary embolism (PE), or death related to VTE — occurred in fewer semuloparin recipients than placebo recipients (1.2% vs. 3.4%; hazard ratio, 0.36; P<0.001). Semuloparin was also associated with significantly lower risk for DVT (odds ratio, 0.32; 95% confidence interval, 0.15–0.62) and PE (OR, 0.41; 95% CI, 0.19–0.85). However, overall survival was similar in both groups. Rates of major bleeding and nonmajor clinically relevant bleeding were low (about 2%), and other adverse events were also similar in both groups.

Comment: The decision to administer anticoagulant prophylaxis to patients receiving chemotherapy is informed by several factors: the nature of the chemotherapy, patient characteristics, tumor type and stage, and the safety and efficacy of available antithrombotic agents. This trial demonstrates that in carefully selected patients with high-risk tumors, LMWH — which is simple to administer without monitoring — safely reduced the incidence of VTE when given concomitantly with chemotherapy.

Source: Journal Watch Oncology and Hematology