US scientists have successfully completed a study where they showed targeted nanoparticles injected directly into a patient’s bloodstream navigated into tumors, delivered double-stranded small interfering RNAs and turned off a gene that drives cancer growth.

The results reported in this study are from a Phase 1 clinical trial that began treating patients with nanoparticles in May 2008. As well as intending to establish scientific proof of concept in humans, like all Phase 1 trials, the goal is to test safety and determine toxicity levels of the therapy. The trial is being sponsored by Calando Pharmaceuticals, a Caltech startup company.

A UCLA statement describes the study as the first to prove that a targeted nanoparticle can be used as an experimental therapeutic in human cancer tumors: it demonstrates the “feasibility of using both nanoparticles and RNA interference-based therapeutics in patients”.

Another first by the team is that they showed the therapeutic can be used in a dose-dependent fashion: the more nanoparticles they injected, the more they found in the cancer cells.

In 2006, American scientists Andrew Fire and Craig Mello won the Nobel Prize for medicine for their discovery of RNA interference (RNAi), the mechanism by which double strands of RNA silence genes by targeting the messenger RNAs (MRNAs) that code proteins.

Fire and Mello first reported their discovery in a 1998 Nature study, and since then there have been high hopes that this way of silencing genes could be developed to treat diseases like cancer.

The reason RNAi could be so powerful is that it does not target a protein directly but the mechanism that codes the protein. Targeting proteins with therapeutics is tricky as often the target areas can be inacessible, perhaps tucked away inside three-dimensional folded structures. But RNAi offers the opportunity to target the mRNA that encodes the information for making the protein: destroy the mRNA and you effectively switch off the corresponding gene and the production of its particular protein.

Lead author Dr Mark E Davis, the Warren and Katharine Schlinger told the press that in principle:

“Every protein now is druggable because its inhibition is accomplished by destroying the mRNA.”

“And we can go after mRNAs in a very designed way, given all the genomic data that are and will become available,” he added.

However, as is often the case, what looks straightforward in theory is fraught with obstacles when you try and apply it in practice. One such difficulty, when trying to apply RNAi technology to humans is, how do you deliver such tiny, fragile molecules, the small interfering RNAs (siRNAs), to the tumors?

Senior author Dr Antoni Ribas,said:

“There are many cancer targets that can be efficiently blocked in the laboratory using siRNA, but blocking them in the clinic has been elusive.”

Davis and colleagues had a solution: they had already been working on ways to deliver nucleic acids into cells before RNAi was discovered. They eventually came up with a method featuring four components, one of which is a unique polymer that can assemble itself into a targeted nanoparticle that carries siRNA.

Davis explained that their nanoparticles can take the siRNAs into the targeted site within the body, and when they reach their target, the cancer cells inside the tumor, the nanoparticles enter the cells and release the siRNAs.

The researchers used a new method developed at Caltech to find and image the nanoparticles inside cells biopsied from the tumors of several patients taking part in the trial.

They also found that the more nanoparticles a patient was given, the more were present in the tumor cells: thus establishing there was a dose-dependent response.

But what was even better, said Davis, was they found evidence the siRNAs had done their job: in the cells they analyzed, which had been targeted to prevent production of the cell-growth protein ribonucleotide reductase, they found the corresponding mRNA had been degraded. Thus effectively the siRNAs had silenced the gene that was fuelling cancer growth.

Davis explained that this was the first time that anyone has found an RNA fragment from patient cells showing that the RNAi mechanism had severed the mRNA at exactly the correct base:

“It proves that the RNA interference mechanism can happen using siRNA in a human,” said Davis.

Ribas said:

“This research provides the first evidence that what works in the lab could help patients in the future by the specific delivery of siRNA using targeted nanoparticles.”

“We can start thinking about targeting the untargetable,” he added.

However, the researchers stressed that while these results are promising, it is still early days and there is a lot of work still to do. However, they are hoping these findings will open the door for future “game-changing” therapeutics that attack cancer and other diseases at the genetic level.

“Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles.”

A new, large-scale study of more than 10,000 adults found that more than one in every 200 asymptomatic people screened with CT colonography, or virtual colonoscopy, had clinically unsuspected malignant cancer and more than half of the cancers were located outside the colon. The findings were published in the April issue of the journal Radiology.

“We are finding that virtual colonoscopy screening actually identifies more unsuspected cancers outside of the colon than within it,” said lead author Perry J. Pickhardt, M.D., professor of radiology and chief of GI Imaging, at the University of Wisconsin School of Medicine & Public Health. “As with asymptomatic colorectal cancers identified by virtual colonoscopy screening, these cancers are often detected at an early, curable stage.”

Colorectal cancer remains the second leading cause of cancer death in the U.S., and the National Cancer Institute estimated that there would be 146,970 new cases diagnosed in 2009 and 49,920 deaths. The disease is largely preventable through screening for colon polyps, which are benign growths that may develop into cancer if not removed. The American Cancer Society recommends that people at average risk for colorectal cancer begin regular colorectal cancer screening at age 50, but current compliance with this recommendation is below 50 percent. Many people resist screening because of the discomfort and inconvenience caused by the conventional optical colonoscopy test.

Virtual colonoscopy is less invasive than optical colonoscopy and produces precise and detailed “fly-through” images of the entire colon’s interior without having to insert a scope. With virtual colonoscopy screening, there is essentially no risk of bleeding or of perforating the colon. There is no need for intravenous sedation, and the procedure is less costly than conventional optical colonoscopy. It also is more convenient, typically taking 10 minutes or less.

Virtual colonoscopy also allows for limited assessment of structures outside the colon (extracolonic), including the abdomen, pelvis and portions of the lungs. Additional diagnostic tests for unsuspected extracolonic findings are performed in about 6 percent of cases, nearly half of which ultimately prove to be clinically relevant.

“Optical colonoscopy cannot provide for any assessment beyond the colon itself, whereas virtual colonoscopy can detect a wide array of unsuspected extracolonic diseases, most notably cancers and aortic aneurysms,” Dr. Pickhardt said.

For the study, Dr. Pickhardt and colleagues set out to determine the detection rate and clinical outcome of unsuspected malignancies detected with virtual colonoscopy in an asymptomatic screening population. The researchers retrospectively reviewed the medical records of 10,286 adults (5,388 men and 4,898 women) with a mean age of 59.8 years who were evaluated at either the University of Wisconsin or National Naval Medical Center. All of the adults had undergone colorectal cancer screening with virtual colonoscopy at the two centers between April 2004 and March 2008. The mean time for follow-up was 30.2 months.

Unsuspected cancer was confirmed in 58 patients, including 33 women and 25 men. Invasive colorectal cancer was found in 22 patients, and extracolonic cancer was found in 36 patients. Cancers in 31 patients (53.4 percent) were stage 1 or localized cancers.

“To our knowledge, none of the patients who presented with stage 1, stage 2 or localized disease at diagnosis has progressed to a higher stage,” Dr. Pickhardt said. “The fact that so many of the cancers in our study were localized or detected at an early stage appears to have positively affected survival.”

Extracolonic malignancies, which outnumbered cases of invasive colorectal cancer, included renal cell carcinoma, lung cancer and non-Hodgkin lymphoma, among others.

“Although extracolonic evaluation at screening CT colonography does carry some disadvantages, such as patient anxiety, inconvenience, or the potential for benign biopsy, our results suggest that early detection of asymptomatic extracolonic cancer represents an additional benefit of screening CT colonography that is not available with optical colonoscopy,” Dr. Pickhardt said.

“Virtual colonoscopy is an accurate, safe and convenient screening test that could potentially be a life-saving examination,” he added.

Sexual problems are frequent after operations for carcinoma of the rectum. Christian Schmidt et al. describe the consequences for quality of life in the current issue of Deutsches Arzteblatt International (Dtsch Arztebl Int 2010; 107[8]: 123-30).

In Germany, each year more than 70,000 people develop colorectal carcinoma. The aim of the study was to investigate the effects of tumor surgery on quality of life and sexual function. Data from 368 patients were available to the authors. The patients were asked the following two questions: “Has the operation resulted in an impairment of your sexuality?” and “How much does this disturb you?”

Men complained increasingly of sexual dysfunction over time and the effects were more marked than in women. Younger female patients had more difficulty in experiencing their sexuality than did older female patients. The probability of loss of function increased with the size of the wound. Radiation and chemotherapy did not have any unfavorable effect on the sex lives of the patients in this study. In spite of the clear results, the authors emphasize that sexual function was not recorded preoperatively, to avoid unsettling the patients. Only cautious conclusions could be drawn from the study.

After making a diagnosis of cancer, clinicians have a number of treatment options. Most of these involve coordinating multiple attacks on the tumor using an arsenal of cancer-killing therapies. Chemotherapy, where toxic drugs are used to specifically kill cancer cells, is a very powerful weapon in this arsenal. It is extremely effective in treating some cancers, such as testicular cancer and Hodgkin’s Disease, but works poorly in other cancer types. Although the reasons for these different responses are complex, one of the known limitations for solid tumors is that sometimes killer drugs injected into the bloodstream are not delivered efficiently to the tumor tissue, and even if they do reach their target, are not retained long enough to administer their lethal hit.

Professor Lisa Coussens and her coworkers, based at the University of California San Francisco Medical Center, have now discovered a way of enhancing drug delivery to tumors: using the cancer’s own architecture to bring about its downfall. Solid tumors need a good blood supply in order to grow, and the blood vessels nourishing the tumors are frequently disorganized and leaky, allowing drugs to leach into the tumor. However, this useful property is counteracted by high tissue pressure within the tumor itself, which creates a barrier for drug uptake. Coussens’ team have found a way of tipping the balance in favor of the blood vessels. Using a mouse model of cancer, they show that blocking the action of a signaling molecule called ALK5 makes tumor blood vessels even leakier for a short period of time, and this window of leakiness can be used to “open up” the tumor for more efficient delivery of drugs.

Coussens’ discovery has exciting implications. Blocking the ALK5 pathway may not only make chemotherapy far more effective in multiple cancers, but could also aid in efficient delivery of the many other therapies that rely on the bloodstream to carry them into a tumor. Further, ALK5 blockade could assist in diagnosis as well as treatment; the imaging molecules used to light up tumors so that they can be seen by scanners might also be able to get in more easily if ALK5 were inactivated at the time of scanning. Together, these benefits may lead to more accurate diagnosis and a far more hopeful prognosis for sufferers of previously intractable solid cancers.

For the first time, scientists have succeeded in growing empty particles derived from a plant virus and have made them carry useful chemicals.

The external surface of these nano containers could be decorated with molecules that guide them to where they are needed in the body, before the chemical load is discharged to exert its effect on diseased cells. The containers are particles of the Cowpea mosaic virus, which is ideally suited for designing biomaterial at the nanoscale.

“This is a shot in the arm for all Cowpea mosaic virus technology,” says Professor George Lomonosoff of the John Innes Centre, one of the authors on a paper to be published in Small.

Scientists have previously tried to empty virus particles of their genetic material using irradiation or chemical treatment. Though successful in rendering the particles non-infectious, these methods have not fully emptied the particles.

Scientists at the John Innes Centre discovered they could assemble empty particles from precursors in plants and then extract them to insert chemicals of interest. Scientists at JIC and elsewhere had also previously managed to decorate the surface of virus particles with useful molecules.

“But now we can load them too, creating fancy chemical containers,” says lead author Dr Dave Evans.

“This brings a huge change to the whole technology and opens up new areas of research,” says Prof Lomonossoff. “We don’t really know all the potential applications yet because such particles have not been available before. There is no history of them.”

One application could be in cancer treatment. Integrins are molecules that appear on cancer cells. The virus particles could be coated externally with peptides that bind to integrins. This would mean the particles seek out cancer cells to the exclusion of healthy cells. Once bound to the cancer cell, the virus particle would release an anti-cancer agent that has been carried as an internal cargo.

Some current drugs damage healthy cells as well as the cancer, leading to hair loss and other side effects. This technology could deliver the drug in a more targeted way.

“The potential for developing Cowpea mosaic virus as a targeted delivery agent of therapeutics is now a reality,” says Dr Evans.

Another weapon in the arsenal against cancer: Nanoparticles that identify, target and kill specific cancer cells while leaving healthy cells alone.

Led by Carl Batt, the Liberty Hyde Bailey Professor of Food Science, the researchers synthesized nanoparticles shaped something like a dumbbell made of gold sandwiched between two pieces of iron oxide. They then attached antibodies, which target a molecule found only in colorectal cancer cells, to the particles. Once bound, the nanoparticles are engulfed by the cancer cells.

To kill the cells, the researchers use a near-infrared laser, which is a wavelength that doesn’t harm normal tissue at the levels used, but the radiation is absorbed by the gold in the nanoparticles. This causes the cancer cells to heat up and die.

“This is a so-called ‘smart’ therapy,” Batt said. “To be a smart therapy, it should be targeted, and it should have some ability to be activated only when it’s there and then kills just the cancer cells.”

The goal, said lead author and biomedical graduate student Dickson Kirui, is to improve the technology and make it suitable for testing in a human clinical trial. The researchers are now working on a similar experiment targeting prostate cancer cells.

“If, down the line, you could clinically just target the cancer cells, you could then spare the health surrounding cells from being harmed that is the critical thing,” Kirui said.

Gold has potential as a material key to fighting cancer in future smart therapies. It is biocompatible, inert and relatively easy to tweak chemically. By changing the size and shape of the gold particle, Kirui and colleagues can tune them to respond to different wavelengths of energy.

Once taken up by the researchers’ gold particles, the cancer cells are destroyed by heat just a few degrees above normal body temperature while the surrounding tissue is left unharmed. Such a low-power laser does not have any effect on surrounding cells because that particular wavelength does not heat up cells if they are not loaded up with nanoparticles, the researchers explained.

Using iron oxide which is basically rust as the other parts of the particles might one day allow scientists to also track the progress of cancer treatments using magnetic resonance imaging, Kirui said, by taking advantage of the particles’ magnetic properties.

A new method of growing arteries could lead to a “biological bypass” – or a non-invasive way to treat coronary artery disease, Yale School of Medicine researchers report with their colleagues in the April issue of Journal of Clinical Investigation.

Coronary arteries can become blocked with plaque, leading to a decrease in the supply of blood and oxygen to the heart. Over time this blockage can lead to debilitating chest pain or heart attack. Severe blockages in multiple major vessels may require coronary artery bypass graft surgery, a major invasive surgery.

“Successfully growing new arteries could provide a biological option for patients facing bypass surgery,” said lead author of the study Michael Simons, M.D., chief of the Section of Cardiology at Yale School of Medicine.

In the past, researchers used growth factors – proteins that stimulate the growth of cells – to grow new arteries, but this method was unsuccessful. Simons and his team studied mice and zebrafish to see if they could simulate arterial formation by switching on and off two signaling pathways – ERK1/2 and P13K.

“We found that there is a cross-talk between the two signaling pathways. One half of the signaling pathway inhibits the other. When we inhibit this mechanism, we are able to grow arteries,” said Simons. “Instead of using growth factors, we stopped the inhibitor mechanism by using a drug that targets a particular enzyme called P13-kinase inhibitor.”

“Because we’ve located this inhibitory pathway, it opens the possibility of developing a new class of medication to grow new arteries,” Simons added. “The next step is to test this finding in a human clinical trial.”

According to a new study, men employed in occupations with potential exposure to high levels of sunlight have a reduced risk of kidney cancer compared with men who were less likely to be exposed to sunlight at work. The study did not find an association between occupational sunlight exposure and kidney cancer risk in women. Published early online in CANCER, a peer-reviewed journal of the American Cancer Society, the study is the largest case-control study of kidney cancer to investigate the association with occupational sunlight exposure. The study, however, did not include information on non-occupational sunlight exposure and does not address directly whether sunlight exposure can help prevent kidney cancer.

Research suggests that vitamin D, which is obtained from sun exposure, some foods, and from supplements, may help prevent some cancers. Vitamin D is metabolized and most active within the kidneys. Because both the incidence of kidney cancer and the prevalence of vitamin D deficiency have increased over the past few decades, Sara Karami, PhD, of the National Cancer Institute in Rockville, MD, and her colleagues designed a study to explore whether occupational sunlight exposure is associated with kidney cancer risk.

The study included 1,097 patients with kidney cancer and 1,476 individuals without cancer from four Central and Eastern European countries. Demographic and lifetime occupational information was collected through in-person interviews and occupational sunlight exposure indices were estimated based on industry and job titles. The investigators observed a 24 percent to 38 percent reduction in kidney cancer risk with increasing occupational sunlight exposure among male participants in the study. No association between occupational sunlight exposure and kidney cancer risk was observed among females in the study.

The findings suggest that sunlight exposure may affect kidney cancer risk, although the authors have no explanation for the apparent differences in risk between men and women. They offer several hypotheses for the observed differences. Biological or behavioral differences between men and women may play a role. For example, hormonal differences may influence the body’s response to sunlight exposure, females may have a higher tendency to use sunscreen on a regular basis, and men may be prone to working outdoors while shirtless. It is also possible that the observed gender differences in risk were due to confounding by other unmeasured kidney cancer risk factors, such as recreational sunlight exposure and physical activity levels.

While this study’s findings raise the possibility of a link between sunlight exposure and kidney cancer risk, “they clearly need to be replicated in other populations and in studies that use better estimates of long-term ultraviolet exposure and vitamin D intake,” said Dr. Karami.

The frequency of post-operative complications following surgery for liver cancer is associated with a hospital having a low volume of liver surgery. Investigators at The Cancer Institute of New Jersey (CINJ) are presenting that finding at the 63rd Annual Society of Surgical Oncology Symposium taking place this week in St. Louis. CINJ is a Center of Excellence of UMDNJ-Robert Wood Johnson Medical School.

Previous analyses of state and national databases have documented institutional volume-related death rates at low-volume hospitals for this type of surgery; however, a causal relationship has not been determined. In this current study, the team analyzed 9,289 cases between 1998 and 2007 from the Nationwide Inpatient Sample database. Patients were more than 18 years old and underwent elective surgical removal of a portion of their liver due to malignancy. A threshold of 20 annual liver surgeries was used in each hospital to separate low-volume facilities from high-volume facilities. Investigators reviewed postoperative complications such as sepsis and hemorrhaging, as well as problems with the liver, lungs, heart, and bladder. Also taken into account were socio-demographic factors such as age, gender and race among other variables.

What they found was that patients at low-volume hospitals experienced at least one of the analyzed postoperative complications more often than at high-volume facilities. Specifically, hemorrhagic, septic and lung complications were more likely to occur at low-volume institutions. However, overall, the rate of liver complications was lower at these facilities. When mortality was analyzed, it was found that patients who underwent liver cancer surgery at low-volume hospitals were 1.4 times as likely to die as patients who had the procedure at a high-volume institution.

Christopher J. Gannon, MD, surgical oncologist at CINJ and assistant professor of surgery at UMDNJ-Robert Wood Johnson Medical School, is the lead investigator. “This new data is significant in that it could be utilized in low-volume facilities to investigate systems problems once complications occur. This information also has benefit for high-volume hospitals, as it could also be used in centralizing liver cancer care,” he noted.

Cholangiocarcinoma (CCA), a bile duct cancer, is one of the major cancers in Northeast Thailand. This cancer is difficult to diagnose and has high metastatic and mortality rates. Overexpression of Met, a hepatocyte growth factor (HGF) receptor, has frequently been found in CCA and is correlated with progression of this type of cancer. HGF/Met activation induces a variety of cellular processes, including cell scattering, invasion and proliferation. Although a number of studies have been reported regarding the correlation between Met expression and CCA, the molecular mechanisms by which HGF induces CCA invasion are not completely understood.

A research article published in the World Journal of Gastroenterology addresses this problem. The research team led by Dr. Suthiphongchai T from Mahidol University used two CCA cell lines overexpressing Met, KKU-M213 and HuCCA-1, to study the role of Met in CCA invasion by activating the Met pathway with HGF. HGF strongly induced invasion and motility of the two CCA cell lines and concomitantly altered E-cadherin localization from membrane to cytosol, but did not affect the levels of secreted MMP-2, MMP-9 or uPA.

Signaling pathways responsible for HGF-induced invasion were further investigated. HGF induced ERK and PI3K/Akt pathways of both CCA cell lines but with different kinetic profiles. HGF induced sustained ERK activation in the KKU-M213 cell line, but transient ERK activation in HuCCA-1 cells. Using specific inhibitors of PI3K and ERK pathways, it was shown that HGF-induced invasion of KKU-M213 was strongly inhibited by both inhibitors, while that of HuCCA-1 was strongly inhibited by PI3K inhibitor but only weakly inhibited by ERK inhibitor. Thus, the signaling pathways responsible for HGF-induced invasiveness of the two CCA cell lines were different, in that PI3K pathway was common for both cell lines, whereas the role of ERK1/2 was likely to be dependent on the duration of ERK1/2 activation.

These results provided more information on the understanding of the signaling mechanisms responsible for HGF-induced CCA invasiveness, which may be helpful for identifying better targets for CCA therapy and for designing appropriate therapeutic strategy to suit each individual patient.