Possible New Cancer Treatment Identified

Article Date: 22 Apr 2012 - 0:00 PDT

New research findings show how it may be possible to render cancer tumours harmless without affecting the other cells and tissues in the body. The findings apply to cancers including breast, lung and bowel cancer. The study was carried out at Lund University in Sweden. 

Many of the most common chemotherapy drugs used to treat cancer have serious side effects because they not only affect the cells in the cancer tumour, but also the cells in the rest of the body. 

Researchers at Lund University have now found a connection between two proteins that in different ways control cell division and the possibilities for a cancer tumour to develop. The retinoblastoma protein obstructs cell division and is absent in most types of cancer tumour. The new findings show that its absence leads to an increase in another protein, gamma-tubulin, which, when present in high levels, encourages the development of cancer tumours. However, if gamma-tubulin is blocked, the tumour cells die while the healthy cells survive. 

The researchers are now looking for substances that can stop the effect of gamma-tubulin on cell division. This could form the basis for a new drug that works on various types of cancer and has a low risk of side effects if the substance is directed to the right place. This is because it is only the tumour cells that die. 

"I judge the chances of finding a basis for a drug to be good, partly because there are already substances that block 'cousins' of gamma-tubulin", says Maria Alvarado-Kristensson, a researcher at Lund University, who believes that, if all goes well, a drug could be ready for initial tests on patients, known as 'phase 1 testing', in 5-6 years' time. 

In the study, tissue and genetic material from patients with various different types of cancer were studied: breast cancer, bladder cancer, small-cell lung cancer, colon cancer and eye cancer. The two proteins were seen to play an important role in all these diseases and the protein is also found in a number of other types of cancer tumour. 

"It is exciting to have research findings that are significant for several common types of cancer. This means that many patients will be affected if our work proves successful", says Maria Alvarado Kristensson. 

The search for effective substances will involve screening a large number of substances, both natural and synthetic. 
http://www.medicalnewstoday.com/releases/244358.php

Novel strategy improves cancer cell uptake of nanoparticles

Posted: Jan 19th, 2012

Novel strategy improves cancer cell uptake of nanoparticles

(Nanowerk News) One of the promises of using nanoparticles to deliver potent anticancer agents to tumors is that it is easy to coat nanoparticles with tumor-targeting molecules that should increase the amount of drug that reaches a tumor while decreasing the amount of drug that hits healthy tissue. Taking this idea one step further, researchers at Harvard Medical School and the Massachusetts Institute of Technology have developed a strategy for identifying what could be called tumor uptake molecules for use on nanoparticles. This new class of tumor-targeting agents boosts the amount of drug-loaded nanoparticles that get into cancer cells.

Omid Farokhzad and Robert Langer, both members of the MIT-Harvard Center for Cancer Nanotechnology Excellence (CCNE), led this study. The researchers published their findings in the journal ACS Nano ("Engineering of Targeted Nanoparticles for Cancer Therapy Using Internalizing Aptamers Isolated by Cell-Uptake Selection").

The MIT-Harvard CCNE team focused their discovery efforts on molecules known as aptamers, which are small pieces of RNA or DNA that form three-dimensional shapes capable of binding tightly and specifically to designated targets. In most instances, aptamers are constructed to target a known biomolecule—a disease-associated protein, for example. In this case, the investigators took a different approach and instead targeted two biological properties—the ability to distinguish a prostate cancer cell from a normal prostate cell and the ability to get into the diseased cells. They performed this feat by starting with a huge pool of random RNA sequences and through an iterative process gradually enriched this pool for RNAs that targeted and entered prostate cancer cells. After 12 cycles of this enrichment process, the investigators identified a small number of aptamers that each displayed superior tumor targeting and uptake properties.

The researchers chose one of these aptamers and linked it to a polymer nanoparticle loaded with docetaxel, a potent anticancer agent. Experiments have so far shown that this construct has no effect on normal cells but is highly toxic to prostate cancer cells. The investigators are planning further studies in animal models of prostate cancer. They note that this approach is easily modified to finding targeting and uptake aptamers for any type of cancer cell.

Source: National Cancer Institute http://www.nanowerk.com/news/newsid=24007.php

Cancer-killing compound spares healthy cells

January 4, 2012

Lithocholic acid (LCA), naturally produced in the liver during digestion, has been seriously underestimated. A study published in the journal Oncotargetshows that LCA can kill several types of cancer cells, such as those found in some brain tumors and breast cancer.

The research team, led by Concordia University, included scientists from McGill University and the Jewish General Hospital's Lady Davis Institute in Montreal as well as the University of Saskatchewan.

Previous research from this same team showed LCA also extends the lifespan of aging yeast. This time, the team found LCA to be very selective in killing cancer cells while leaving normal cells unscathed. This could signal a huge improvement over the baby-with-the-bathwater drugs used in chemotherapy.

"LCA doesn't just kill individual cancer cells. It could also prevent the entire tumor from growing," says senior author Vladimir Titorenko, a professor in the Department of Biology and Concordia University Research Chair in Genomics, Cell Biology and Aging.

What's more, LCA prevents tumors from releasing substances that cause neighboring cancer cells to grow and proliferate. Titorenko says LCA is the only compound that targets cancer cells, which could translate into tumor-halting power.

"This is important for preventing cancer cells from spreading to other parts of the body," he says, noting that unlike other anti-aging compounds, LCA stops cancer cell growth yet lets normal cells continue to grow.

A wide effect on different types of cancers

The next step for the research team will be to test LCA's effect on different cancers in mice models. Titorenko expects that LCA will also kill cancer cells in those experiments and lead to human clinical trials. "Our study found that LCA kills not only tumors (neuroblastomas), but also human breast cancer cells," says Titorenko. "This shows that it has a wide effect on different types of cancers."

Titorenko emphasizes that unlike drugs used in chemotherapy, LCA is a natural compound that is already present in our bodies. Studies have shown that LCA can be safely administered to mice by adding it to their food. So why is LCA so deadly for cancer cells? Titorenko speculates that cancer cells have more sensors for LCA, which makes them more sensitive to the compound than normal cells.

LCA sensors send signals to mitochondria — the powerhouses of all cells. It seems that when these signals are too strong, mitochondria self-destruct and bring the cell down with them. Simply put, Titorenko and his colleagues engaged in cancer cell sabotage by targeting a weakness to LCA.

More information: http://spectrum.li … dia.ca/36018

Provided by Concordia University

http://medicalxpress.com/news/2012-01-cancer-killing-compound-healthy-cells.html

Lithocholic bile acid selectively kills neuroblastoma cells, while sparing normal neuronal cells

http://spectrum.library.concordia.ca/36018/1/Titorenko_Oncotarget_2011.pdf

'Good Cholesterol' Nanoparticles Seek and Destroy Cancer Cells

ScienceDaily (Apr. 1, 2011) — High-density lipoprotein's hauls excess cholesterol to the liver for disposal, but new research suggests "good cholesterol" can also act as a special delivery vehicle of destruction for cancer.

Synthetic HDL nanoparticles loaded with small interfering RNA to silence cancer-promoting genes selectively shrunk or destroyed ovarian cancer tumors in mice, a research team led by scientists from The University of Texas MD Anderson Cancer Center and the University of North Texas Health Science Center reports in the April edition of Neoplasia.

"RNA interference has great therapeutic potential but delivering it to cancer cells has been problematic," said Anil Sood, M.D., the study's senior author and MD Anderson's director of Ovarian Cancer Research and co-director of the Center for RNA Interference and Non-Coding RNA at MD Anderson. "Combining siRNA with HDL provides an efficient way to get these molecules to their targets. This study has several important implications in the ability to fight certain cancers."

Sood and Andras Lacko, Ph.D., professor of Molecular Biology and Immunology at UNT Health Science Center, jointly developed the nanoparticles, which build on Lacko's original insight about HDL's potential for cancer drug delivery.

The next step is to prepare for human clinical trials, the two scientists said. "If we can knock out 70, 80 or 90 percent of tumors without drug accumulation in normal tissues in mice, it is likely that many cancer patients could benefit from this new type of treatment in the long run," Lacko said.

Only cancer and liver cells express HDL receptor

Previous studies have shown that cancer cells attract and scavenge HDL by producing high levels of its receptor, SR-B1. As cancer cells take in HDL, they grow and proliferate. The only other site in the body that makes SR-B1 receptor is the liver. This selectivity for cancer cells protects normal, healthy cells from side effects.

Previous attempts to deliver siRNA by lipsomes and other nanoparticles have been hampered by toxicity and other concerns. The tiny bits of RNA, which regulate genes in a highly targeted fashion, can't simply be injected, for example.

"If siRNA is not in a nanoparticle, it gets broken down and excreted before it can be effective," Sood said. "HDL is completely biocompatible and is a safety improvement over other types of nanoparticles."

The team developed a synthetic version of HDL, called rHDL, because it's more stable than the natural version.

Fewer and smaller tumors, less toxicity

Using rHDL as a delivery method has other advantages as well. rHDL has not shown to cause immunologic responses, helping to minimize potential side effects, Lacko said, and it exhibits longer time in circulation than other drug formulations or lipoproteins. Also, because SR-B1 is found only in the liver, an rHDL vehicle will help block and treat metastasis to that organ.

Researchers first confirmed the distribution of SR-B1 and the uptake of rHDL nanoparticles in mice injected with cancer cells. They found that siRNA was distributed evenly in about 80 percent of a treated tumor. As expected, the nanoparticles accumulated in the liver with minimal or no delivery to the brain, heart, lung, kidney or spleen. Safety studies showed uptake in the liver did not cause adverse effects.

Using siRNA tailored to the individual gene, the researchers separately shut down the genes STAT3 and FAK in various types of treatment-resistant ovarian cancer tumors. STAT3 and FAK are important to cancer growth, progression and metastasis; however, they also play important roles in normal tissue so targeting precision is vital.

The siRNA/rHDL formulation alone reduced the size and number of tumors by 60 to 80 percent. Combinations with chemotherapy caused reductions above 90 percent.

Conventional approaches to target STAT3 have met limited success, Sood said. FAK, which is over expressed in colorectal, breast, ovarian, thyroid and prostate cancers, is particularly aggressive in ovarian cancer and one reason for its poor survival rate. While previous attempts have targeted FAK with liposomal nanoparticles or small molecule inhibitors, these methods are not tumor-specific and are more likely to harm normal cells, the scientists noted.

Next Step: Clinical Studies

"In order to help expedite the study's progress to a clinical setting, we have identified 12 genes as biomarkers for response to STAT3-targeted therapy," Sood said. "Next, we'll work with the National Cancer Institute Nanoparticle Characterization Lab to develop a formulation of the HDL/siRNA nanoparticle for human use."

MD Anderson and UNT have applied for a patent for the nanoparticle delivery method. These arrangements are managed by MD Anderson and the University of North Texas HSC in accordance with institutional conflict of interest policies.

This research was supported by grants from GCF Molly-Cade, National Institutes of Health, U.S. Department of Defense, Ovarian Cancer Research Fund, Inc., Zarrow Foundation, The Marcus Foundation, the University of Texas MD Anderson Cancer Center SPORE in Ovarian Cancer, the Betty Ann Asche Murray Distinguished Professorship, Deborah Gonzalez Women's Health Fellowship Award, the Puerto Rico Comprehensive Cancer Center, Cowtown Cruisin' for the Cure and a HER grant from the University of North Texas Health Science Center.
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The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by University of Texas M. D. Anderson Cancer Center.

Journal Reference:

Mian M.K. Shahzad, Lingegowda S. Mangala, Hee D. Han, Chunhua Lu, Justin Bottsford-Miller, Edna M. Mora, Jeong W. Lee, Rebecca L. Stone, Duangmani Thanapprapasr, Ju-Won Roh, Puja Gaur, Maya P. Nair, Yun Y. Park, Nirupama Sabnis, Michael T. Deavers, Ju-Seog Lee, Lee M. Ellis, Gabriel Lopez-Berestein, Walter J. McConathy, Laszlo Prokai, Andras G. Lacko and Anil K Sood. Targeted Delivery of Small Interfering RNA Using rHDL Nanoparticles. Neoplasia, Year 2011, Volume 13, Issue 4 [http://www.neoplasia.com/abstract.php?msid=3961]

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