Targeted cancer therapy kills prostate tumor cells, study finds

ScienceDaily (June 6, 2011) — A new targeted therapy for prostate cancer halts tumor growth in animals with advanced prostate cancer that is resistant to hormone therapy, a new study finds.

See Also:Health & MedicineProstate CancerMen's HealthProstate HealthUrologyCancerBreast CancerReferenceMetastasisEmbryonic stem cellUrologyTumor suppressor gene

The results are being presented at The Endocrine Society's 93rd Annual Meeting in Boston.

"This targeted therapy may provide a treatment breakthrough that will extend the lives of men with advanced, hormone-refractory prostate cancer," said lead investigator Shuk-mei Ho, PhD, chairwoman of the Department of Environmental Health at the University of Cincinnati.

Men with prostate cancer that has recurred or has spread outside the prostate routinely receive androgen deprivation therapy, which blocks the action of the male hormones. This castration occurs through surgical removal of both testes or more often with medications. Although effective, this hormone-blocking treatment eventually stops working in some patients, Ho said.

"These patients are left with very few treatment options and usually succumb quickly to the disease," she said.

Ho's team previously found they can inhibit the growth of prostate cancer cell lines in culture by targeting and activating a protein called G protein-coupled receptor 30 (GPR30) using the experimental drug G-1, a GPR30 agonist, or stimulator.

In their new study, funded by the Veterans Affairs and the National Institutes of Health, Ho and her co-workers tested G-1 in an animal model of castration-resistant prostate cancer. They implanted human prostate cancer cells beneath the skin of male mice. The established tumor regressed upon castration and after the cancer relapsed, they injected the mice with a low dose of G-1. They also gave G-1 to noncastrated, or "intact," male mice that had prostate tumors. In these intact mice that still had male hormones, G-1 did not stop growth of the prostate tumors or cause substantial death of tumor cells (necrosis), they found.

"Surprisingly, G-1 was highly effective in halting the growth of the tumors that re-emerged after castration," Ho said.

The castration-resistant tumors showed a 65 percent necrosis. These mice had increased expression of GPR30 after castration, which Ho believes sensitized prostate tumors to the cell growth-inhibiting effects of G-1.

"These results mean G-1 won't work without androgen deprivation therapy," she said.

Therefore, Ho reported, the window of time when this targeted therapy might be effective for treating hormone-resistant prostate cancer is after androgen deprivation therapy. She said she believes G-1 can make androgen blockade more effective. G-1 caused no harm to the prostate or other vital organs in mice, she added.

Although GPR30 may have a role in cell growth in female tissues, Ho said it appears to have the opposite effect in men with hormone-resistant prostate cancer. "The beauty of this GPR30 is that it does not have any estrogen, and so it will not cause any side effects of estrogen," she said.

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Immune cells link pregnancy and tumor spread

ScienceDaily (June 6, 2011) — Individuals with cancer often do not die as a result of their initial tumor but as a result of tumors at distant sites that are derived from the initial tumor. Pregnancy is a condition that seems to be permissive for tumor dissemination, as breast tumors arising during pregnancy display a tendency for early spread to distant sites (metastasis). Research in mice, led by Ivan Stamenkovic, at the University of Lausanne, Switzerland, has now uncovered a possible reason for this.

See Also:Health & MedicineBrain TumorCancerLung CancerStem CellsImmune SystemProstate CancerReferenceMetastasisTumor suppressor geneTumorLeukemia

Stamenkovic and colleagues found that the increased metastasis from tumors of several different types that they observed in pregnant mice was a result of decreased activity of immune cells known as NK cells. Furthermore, at least part of the inhibitory effect on NK cells was mediated by another group of immune cells, myeloid-derived suppressor cells. Consistent with this, the gene expression profile of the lungs of pregnant mice (a site to which many of the tumors metastasized) was reflective of myeloid-derived suppressor cell accumulation.

Of clinical interest, the majority of genes downregulated in the lungs of pregnant mice were also expressed at lower levels in samples from lung cancer patients with poor prognosis than in samples from patients with better prognosis. The authors therefore suggest that myeloid-derived suppressor cells may represent a shared mechanism of immune suppression during pregnancy and tumor growth.

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Novel imaging agent targets breast tumor development

ScienceDaily (June 6, 2011) — Scientists presented new research at SNM's 58th Annual Meeting that has the potential to help physicians detect breast cancer by imaging the proliferation of blood vessels carrying oxygen and nutrients to breast tumors. Their study is evaluating a new imaging agent that is naturally drawn to angiogenesis -- the development of new blood vessels in tissues both normal and cancerous. This process turns malignant during the growth stage of many cancerous tumors including those in breast tissue.

See Also:Health & MedicineBreast CancerMedical ImagingCancerWomen's HealthBrain TumorBreastfeedingReferenceMetastasisInterventional radiologyPositron emission tomographyMammography

"The positive outcomes of this study are encouraging and may provide clinicians with additional information for breast cancer management," says Andrei Iagaru, MD, lead author of the study and assistant professor of radiology and nuclear medicine at Stanford University Medical Center, Stanford, Calif. "PET imaging with this agent could potentially lead to better clinical decisions; patients with progressive cancer who are ideal candidates for aggressive therapies could be identified earlier to improve their prognosis."

The new imaging agent central to this study is called 18F FPPRGD2, which combines the medical isotope fluorine-18 (18F) with a protein biomarker ideal for imaging the expression of an integrin known as αvβ3. Integrins are essentially protein-based receptors that regulate the adhesion between cells and connecting tissues. They are also involved in cell signaling, which mediates a cell's shape, movement and lifecycle, but their most useful trait is their key involvement in angiogenesis. Upon injection the agent seeks out tissues in a state of angiogenesis and is then captured using a molecular imaging technique known as positron emission tomography (PET), which produces functional imaging of the body.

Six female participants with breast cancer were recruited for the study and were imaged twice using 18F FPPRGD2 and 18F FDG PET/CT within two weeks. PET imaging with 18F FPPRGD2 showed superior functionality for identifying angiogenesis in breast tissue, with strong uptake and distribution in both primary cancers and metastatic lesions.

Further studies evaluating the effectiveness of 18F FPPRGD2 for targeting breast tumor angiogenesis could lead to its availability for clinical use for patients known to have breast cancer. This agent could be an effective tool for cancer staging and may improve patient treatment planning as a result of the information it provides. Preliminary findings show that it could become a useful weapon in the fight against breast cancer.

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Gamma imaging provides superior tumor detection for dense breasts

ScienceDaily (June 6, 2011) — A study revealed at SNM's 58th Annual Meeting is comparing the breast-tumor detection capabilities of two very different imaging technologies -- breast-specific gamma imaging (BSGI), which provides functional images of breast physiology, and ultrasound -- for women with complex breast imaging cases that require further evaluation. Many women who have dense breast tissue (radiodense breasts) are difficult to image using mammography, currently the gold standard of breast imaging. For women whose mammograms are not clear enough to determine whether cancer is present, support methods such as BSGI and ultrasound are used to answer any remaining diagnostic questions.

See Also:Health & MedicineBreast CancerWomen's HealthCancerMedical ImagingBreastfeedingDiseases and ConditionsReferenceMammographyBreast reconstructionBreast cancerMetastasis

"A lot of white shows up on the mammograms of women with radiodense breasts, and it becomes a lot like trying to find one cloud in a cloudy sky," says Douglas Kieper, BSNMT, professor and nuclear medicine research supervisor at Hampton University, Hampton, Va. "This study tells us that BSGI improves our ability to detect breast cancer when combined with other breast imaging techniques. What we are really looking at is the impact that BSGI and ultrasound have on breast cancer patient management. Comprehensive breast imaging including BSGI could improve breast cancer detection and provide a better prognosis for breast cancer patients."

According to the American Cancer Society, breast cancer is the foremost form of cancer developed by women, except for skin cancer. An estimated 207,090 women were diagnosed with breast cancer and approximately 39,840 died of the disease in 2010. Current statistics estimate that a woman's chance of developing the disease is slightly less than one in eight women. Mammography catches about 85 percent of breast cancers in women with normal breast tissue but only 60 percent in women with dense breast tissue. Instead of relaying information about the structure or anatomy as mammography and ultrasound imaging do, BSGI informs clinicians about functions of the breast tissues, specifically changes in tumor tissues that could be essential to appropriate treatment planning, whether for biopsy, lumpectomy or cancer therapy.

BSGI, also known as molecular breast imaging, is most valuable for women who have an unresolved diagnostic concerns after mammography. These are often labeled as BIRADS 0 mammograms according to the Breast Imaging Reporting and Data System. Breast cancer patients receive a score that assesses cancer in the range of one to six, the latter being confirmed malignancy. BIRADS 0 means that there is insufficient information and further evaluation is necessary, whether the patient has dense breasts, had negative results during a mammogram but nipple discharge, or has a family history of breast cancer.

For this study, 119 patients from four medical centers scheduled for BSGI evaluation were added to a registry, and results of their routine exams were collected for analysis. Results of both routine BSGI and ultrasound imaging were collected and compared for their ability to provide additional information about the case and change breast cancer patient management. Of the 119 subjects, 102 lesions were benign, 25 were malignant and 2 were labeled as high-risk for cancer. BSGI changed the diagnosis for 109 participants compared to ultrasound, which changed patient management in 71 cases. BSGI offered greater sensitivity for detecting breast cancer (100 percent versus 77 percent with ultrasound) and greater specificity, being negative in benign cases (82 percent versus 52 percent of cases with ultrasound).

Molecular breast imaging is continually expanding. If future studies also prove that BSGI imaging is clinically useful for patient management and the cost of technology and radiation dose are reduced with technological advancements, BSGI could potentially become an accepted imaging technique for initial cancer screening. Until then, BSGI is an effective tool for providing clinicians with additional information about complex breast cancer cases and could potentially improve cancer outcomes for women.

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New 3-D tumor model: Step toward speeding cancer drug research

ScienceDaily (June 8, 2011) — A team of scientists has developed a way to coax tumor cells in the lab to grow into 3-D spheres. Their discovery takes advantage of an earlier technique of producing spherical cavities in a common polymer and promises more accurate tests of new cancer therapies.

See Also:Health & MedicineLung CancerBrain TumorCancerMatter & EnergyPhysicsGrapheneMaterials ScienceReferenceNanomedicineMetastasisTumor suppressor geneTumor

As team leader Michael R. King, Ph.D., of Cornell University explains, "Sometimes engineering research tends to be a case of a hammer looking for a nail. We knew our previous discovery was new and it was cool. And now we know it's useful."

Three years ago, the team -- in collaboration with Lisa DeLouise, Ph.D., MPD, of Rochester, N.Y. -- perfected a low-cost, easy fabrication technique to make spherical cavities in PDMS (polydimethylsiloxane), a widely used silicon organic polymer. More recently, the Cornell team discovered that these cavities could be used as a scaffolding to grow numerous tumor spheroids, which could serve as realistic models for cancer cells. The Cornell team's work appears in the current issue of Biomicrofluidics, a publication of the American Institute of Physics.

The three-dimensional spheroids hold the potential to speed cancer drug discovery by providing a realistic and easily accessible substrate on which to test drugs. Their 3-D nature is an asset because in the body, tumor cells grow in 3-D -- yet most laboratory studies of cancer have been done in 2-D, with a single layer of cancer cells grown on the bottom of a petri dish. Too often a promising 2-D drug candidate fails when it enters the 3-D stage of animal testing. The new 3-D tumor spheroids may help eliminate that problem. They also offer a realistic tumor oxygen environment that cues the blood vessel growth that nourishes tumors -- an appealing target for anti-cancer drug design.

"Basically, any laboratory that works with cells could adopt our new spherical microcavity system to do their own 3-D experiments or drug screening on hundreds or even thousands of little tumor spheroids," said King.

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Iron key to brain tumor drug delivery

ScienceDaily (June 2, 2011) — Brain cancer therapy may be more effective if the expression of an iron-storing protein is decreased to enhance the action of therapeutic drugs on brain cancer cells, according to Penn State College of Medicine researchers.

See Also:Health & MedicineBrain TumorColon CancerLung CancerMind & BrainBrain InjuryIntelligenceNeuroscienceReferenceMetastasisTumor suppressor geneGliomaTumor

Malignant glioblastoma multiforme is a deadly brain tumor for which no long-term effective cure exists. Because drugs in the blood do not pass from the blood vessels to the brain, effective amounts of chemotherapy drugs do not reach the tumor. Increasing dosages damage normal brain tissue and cause significant neurological damage. These dosages also would likely be harmful to other organs in the body. However, by increasing the sensitivity of the cancer cells to drugs, the effectiveness of treatment can be increased.

"About half of all brain tumors are resistant to chemotherapy and new therapeutic strategies are urgently needed to treat this cancer," said James Connor, Ph.D., Distinguished Professor and vice-chairman of neurosurgery.

Connor and his graduate student Xiaoli Liu took advantage of the high iron requirements of the brain cancer cells to target ferritin, a protein that stores iron in all cells.

"High levels of iron are required in cancer cells to meet the energy requirements associated with their rapid growth," Connor said. "In addition, iron is essential for general cell health."

Working with Achuthamangalam Madhankumar, Ph.D., assistant professor of neurosurgery, the researchers used liposomes -- tiny lipid containers -- to deliver a fragment of RNA called interference or siRNA, to tumor cells. The siRNA targets the molecular machinery of the cell so that the protein cannot be made -- a process known as downregulation. By targeting and turning off ferritin in cancer cells, the protective function of H-ferritin disappears and the sensitivity to chemotherapy increases.

Using ferritin siRNA, the protein level decreases by 80 percent within 48 hours providing a window of opportunity for enhanced sensitivity to the chemotherapeutic agent. The researchers studied whether silencing ferritin would lower the effective dosage of BCNU, a chemotherapy drug used in brain tumor treatment and one of the few approved for brain cancer. While BCNU is effective, it has serious side effects limiting its use.

The use of siRNA reduces the amount of BCNU needed for tumor suppression by more than half in mice, according to the researchers, who published their findings in the journal Cancer Research.

"Our results further indicate that a nanoliposomal delivery mechanism can increase the efficacy of siRNA and optimize the amount of siRNA delivered," Connor said. "By silencing the ferritin gene, tumor sensitivity to chemotoxins was increased. The results from this project are a promising initial step toward the development of siRNA gene therapy involving ferritin for the treatment of multiple tumor types."

Other researchers contributing to this project were Becky Slagle-Webb, research assistant, and Jonas M. Sheehan, M.D., associate professor of neurosurgery, Penn State College of Medicine and Nodar Surguladze, Ph.D., deputy director, Institute of Molecular Biology and Biological Physics, Republic of Georgia.

The Tara Leah Witmer Foundation partially supported this research.

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