New computational model could design medications like chemotherapy with fewer side effects

Medications, such as chemotherapy, are often limited by their tendency to be detrimental to healthy cells as an unintended side effect. Now research in the Cell Press’s Biophysical Journal offers a new computational model that can help investigators design ways to direct drugs to their specific targets.

A major problem with many cancer drugs is the harmful effects they can have on normal cells. Similarly, treatments for a variety of other diseases can have side effects by acting on cells that are not meant to be targeted. Researchers have tried to overcome this by linking drugs to antibodies, for example by linking a chemotherapy agent to an antibody that specifically attaches to cancer cells to create a fusion protein. However, it can be difficult to do so without compromising the medication’s effectiveness because the drug has to be able to reach its targeted cell receptor at the same time as the antibody binds to its own target on the cell.

Investigators have now developed a computational model to help design the most effective way to link an antibody to a therapeutic drug to create such a fusion protein. The model takes into consideration how the length of an antibody linker will affect a drug’s ability to interact with its target and uses this information as well as other parameters to model and predict how a particular fusion protein will look geometrically, how it will act when applied to cells, and what concentration is optimal.

The importance of this finding is that it has the potential to allow us to predict the behavior of fusion proteins without having to physically make them, eliminating unsuccessful candidates for drug design using modeling and thereby saving time and effort,” explains senior author Dr. Pamela Silver, of Harvard Medical School and the Wyss Institute for Biologically Inspired Engineering at Harvard University. Therefore, accurately modeling the behavior associated with a given design for a fusion protein could allow researchers to move away from a screening-based, guess-and-check method to one that is based on rational design. “Using modeling as a first step of validation will allow us to determine which constructs are likely to be promising and focus our efforts on the best candidates for testing,” says lead author Dr. Avi Robinson-Mosher, of the Wyss Institute.

The scientists verified their approach by creating various geometric combinations of antibody fragments and therapeutic molecules with linkers of different lengths, then successfully demonstrated that each fusion protein’s effectiveness could be predicted through their model.

This study is important because it provides a roadmap for how to design more selective, less toxic chemotherapies,” adds Dr. Leslie Loew, Director of the R. D. Berlin Center for Cell Analysis and Modeling at the University of Connecticut Health Center and Editor in Chief of Biophysical Journal. “It is especially impressive that these researchers not only developed very elegant computational models, but then went to the lab to verify the predictions with experiments.”

Robinson-Mosher et al. Designing cell targeted therapeutic proteins reveals the interplay between domain connectivity and cell binding. Biophys J. 2014;107(10):2456–2466 DOI: http://dx.doi.org/10.1016/j.bpj.2014.10.007 [Abstract]

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Race, hospital, insurance status all factors in how lung cancer is treated

African Americans, Hispanics, and those who receive care at a community hospital are all significantly less likely than other patients to receive treatment for early stage non-small cell lung cancer, according to a report in the Journal of Thoracic Oncology.

We found significant disparities for treatment of a curable cancer based on race, insurance status, and whether or not treatment was at an academic or community hospital,” said Dr. Matthew Koshy, a physician in the department of radiation oncology at the University of Illinois at Chicago College of Medicine, and lead author of the study. “Reducing these disparities could lead to significant improvements in survival for many people with inoperable early stage lung cancer.

The study is the largest to date looking at treatment received by patients with stage I non-small cell lung cancer, an early stage of lung cancer that has not spread to the lymph nodes and is characterized by a small nodules in the lung tissue. Treatment during this early stage offers the best chance for long-term survival.

Surgery to remove cancerous nodules in the lungs is the standard treatment for patients with stage I NSCLC. But many patients cannot undergo surgery, due to complicating medical conditions such as poor lung function or heart disease.

For those patients, radiation therapy has been the standard treatment, but outcomes are much poorer than for surgical treatment. Many patients deemed inoperable are only monitored, because the benefits of conventional radiation are regarded as minimal.

Over the last 10 years, a new radiation technology called stereotactic body radiotherapy, or SBRT, has replaced conventional radiation as the standard treatment for inoperable stage I NSCLC. It delivers much higher doses of radiation, requires fewer treatments, is better tolerated, and has survival outcomes comparable to surgery.

Koshy and his colleagues wanted to know if any factors predicted whether a patient was more likely to be observed, treated with conventional radiation, or treated with SBRT — and if there were any disparities in the use of those treatments.

They looked at data from nearly 40,000 patients with inoperable stage I NSCLC added to the National Cancer Database between 2003 and 2011. The hospital-based cancer registry collects information on patient demographics, insurance status, diagnosis, treatment and outcome.

The analysis showed that African Americans were 40 percent less likely, and Hispanics 60 percent less likely, to be treated with radiation — either conventional radiation or SBRT. Of patients who did receive radiation, African Americans and those with no insurance were less likely to receive SBRT.

Patients were two-and-a-half times more likely to receive SBRT in academic hospitals than in community hospitals, and seven times more likely to receive SBRT at a high-volume medical center than at a low-volume center.

The researchers found that in 2011, 46 percent of patients receiving care in community care centers were only observed, compared to 21 percent of patients at academic medical centers. Sixty-eight percent of patients at academic medical centers received SBRT compared to 25 percent of patients at community hospitals.

Koshy suggests that all patients with early stage inoperable lung cancer be evaluated by a radiation oncologist, and that more radiation oncologists trained in SBRT are needed. Better access to facilities that offer SBRT could help reduce the disparities the study uncovered, he said.

Koshy et al. Disparities in Treatment of Patients with Inoperable Stage I Non-Small Cell Lung Cancer: A Population-Based Analysis. J Thorac Oncol. 2014; EPub Ahead of Print. doi: 10.1097/JTO.0000000000000418 [Abstract]

Practice makes perfect in cancer surgery

Researchers determine higher hospital and surgeon volume lead to better outcomes when treating bladder cancer patients

In a new, in-depth research project, Queen’s professors Rob Siemens (Urology) and Christopher Booth (Cancer Care and Epidemiology) investigated what affect higher volume hospitals and surgeons had on the outcomes of patients undergoing a radical cystectomy for bladder cancer in Ontario.

Using data provided by the Institute for Clinical Evaluative Sciences (ICES) the investigators studied 2,802 patients who underwent the procedure between 1994 and 2008 in Ontario and found that higher volume hospital and surgeons were associated with less post-operative complications and better overall survival.

These results are intriguing and will undoubtedly lead to some controversy in their interpretation,” says Dr. Siemens. “We wondered if the processes and interactions that lead to better outcomes for patients treated by higher volume providers can be studied and identified, perhaps leading to improved outcomes for all if adopted by lower volume hospitals and surgeons.

The recent study explored a number of different aspects of bladder cancer care to better understand how quality surgical care is delivered for patients with advanced bladder cancer. The explanations for this volume-outcome relationship still remain mostly unidentified which could be a research project in the future.

This research has only been able to illuminate a small fraction of the factors that explain the improved outcomes of higher volume providers,” says Dr. Siemens. “Some would interpret this as a call to more aggressively support a policy of centralizing care at higher volume hospitals for complex medical/surgical diseases.

Siemens et al., (2014). Processes of Care and the Impact of Surgical Volumes on Cancer-specific Survival: A Population-based Study in Bladder Cancer. Urology, 84: 1049–1057 [Abstract]

Integrative medicine relieves pain and anxiety for patients with cancer

Pain is a common symptom of cancer and side effect of cancer treatment, and treating cancer-related pain is often a challenge for health care providers. The Penny George Institute for Health and Healing researchers found that integrative medicine therapies can substantially decrease pain and anxiety for hospitalized cancer patients. Their findings are published in the Journal of the National Cancer Institute Monographs.

Following Integrative medicine interventions, such as medical massage, acupuncture, guided imagery or relaxation response intervention, cancer patients experienced a reduction in pain by an average of 47 percent and anxiety by 56 percent,” said Jill Johnson, Ph.D., M.P.H., lead author and Senior Scientific Advisor at the Penny George Institute.

The size of these reductions is clinically important, because theoretically, these therapies can be as effective as medications, which is the next step of our research,” said Jeffery Dusek, Ph.D., senior author and Research Director for the Penny George Institute.

The Penny George Institute receives funding from the National Center of Alternative and Complementary Medicine of the National Institutes of Health to study the impact of integrative therapies on pain over many hours as well as over the course of a patient’s entire hospital stay.

The overall goal of this research is to determine how integrative services can be used with or instead of narcotic medications to control pain,” Johnson said.

Researchers looked at electronic medical records from admissions at Abbott Northwestern Hospital between July 1, 2009 and December 31, 2012. From more than ten thousand admissions, researchers identified 1,833 in which cancer patients received integrative medicine services.

Patients were asked to report their pain and anxiety before and just after the integrative medicine intervention, which averaged 30 minutes in duration. Patients being treated for lung, bronchus, and trachea cancers showed the largest percentage decrease in pain (51 percent). Patients with prostate cancer reported the largest percentage decrease in anxiety (64 percent).

Johnson et al., (2014). Effects of Integrative Medicine on Pain and Anxiety Among Oncology Inpatients. J. Natl. Cancer Inst. Monogr., 50: 330-337, doi: 10.1093/jncimonographs/lgu030 [Abstract]

New research gives insight into breast cancer recurrence

Around 5,000 cases of ductal carcinoma in situ (DCIS), a condition where cancerous cells are contained within the milk ducts of the breast, are diagnosed each year in the UK, with two thirds diagnosed through breast screening. If left untreated, up to half of DCIS cases could progress into invasive breast cancer, but it is not possible to say which ones, so all women are offered treatment.

This usually involves breast-conserving surgery (lumpectomy) and, to reduce the risk of the cancer returning, radiotherapy to kill any remaining cancer cells. Even with treatment, however, up to one in five patients will see their DCIS come back, either as DCIS or as invasive breast cancer.

Now researchers from The University of Manchester and University Hospital of South Manchester NHS Foundation Trust – both part of the Manchester Cancer Research Centre – have investigated the role of a molecule known as  focal adhesion kinase (FAK) in controlling the resistance of DCIS to radiation and in predicting disease recurrence.

Dr Gillian Farnie, whose work at the University’s Institute of Cancer Sciences was funded by a five-year £500,000 Breast Cancer Campaign Scientific Fellowship, said: “We know that cancer stem cells are able to avoid or repair damage caused by treatment. We wanted to look at how FAK is involved in this treatment resistance.”

The team found that cancer cell samples containing more cancer stem cells had increased levels of FAK and that these samples were better able to survive radiotherapy. By examining patient tissue samples and information about whether each person had had a recurrence, the scientists discovered that high FAK activity was linked to the disease returning, either as DCIS or invasive breast cancer.

In further work, a drug that blocks FAK reduced the formation of mammospheres, or clumps of breast cancer stem cells, showing FAK is important in cancer stem cell activity. By combining this inhibition of FAK with radiotherapy, the group was able to achieve a greater treatment effect than with either therapy alone.

To see if the FAK drug works in more complex living systems, the researchers gave mice with DCIS a treatment to block FAK. In treated mice the DCIS were less likely to turn into invasive-like cancer cells showing FAK is important in the progression of DCIS to invasive cancer.

We have shown that blocking the activity of FAK not only reduces the growth of breast cancer stem cells, but also improves sensitivity to radiotherapy. Our findings suggest we can reduce the likelihood of DCIS recurring by inhibiting FAK and measuring FAK levels could offer a method to predict which patients are most likely to experience recurrence,” added Dr Farnie.

Katherine Woods, Research Communications Manager at Breast Cancer Campaign, said: “There is still so much we don’t know about DCIS. It is vital that we get a better understanding of the biology of DCIS as well as what makes it return in some women and become invasive breast cancer.

This knowledge could help doctors avoid over-treating those patients whose DCIS won’t come back, while making sure treatment is working for women who need it. Dr Farnie’s research is an important step in this direction, and we are excited to see how the next stages progress.”

Dr Farnie and colleagues have also provided further evidence that cancer stem cells seem be helping cancers to survive treatment. This is a fascinating new field of thought in breast cancer research, especially given the team’s findings that we might be able to stop cancer stem cells by blocking the molecule FAK.”

Williams et al., (2014). Focal adhesion kinase and wnt signalling regulates human ductal carcinoma in situ stem cell activity and response to radiotherapy. Stem Cells,  doi: 10.1002/stem.1843. Epub Ahead of Print [Abstract]