“It is a team approach that can include physicians, scientists, molecular biologists, biologists, chemists and pharmacologists, all whom are trying get a real picture of what patients need and applying the most advanced scientific techniques to meet those needs,” she says. “For integrated approaches that we use at Charles River, we are taking the clinical teams and looking three or four years ahead into cancer drug development and what is currently in clinical trials, where the biology is and looking at what we need to do preclinically to prepare for the next clinical trial. How we do that is to use both benchtop science, such as in vitro assays, cell-based assays and chemical-based assays, as well as animal models of cancer and apply this current standard of care to the models.”

 

Often, pharma gets a bad rap for not working together. Hollister says the integrated approach goes a long way in dispelling those preconceived notions.

 

The impression is similar for Robert Shorr, CEO of Cornerstone Pharmaceuticals, who says he views integrated approaches to cancer research as the convergence of a variety of often disparate disciplines and areas of expertise working together to improve cancer treatment. 

 

“Many scientists and oncologists see cancer as many different diseases, since different types of cancer originate from genetically diverse sources and show genotypic and phenotypic differences,” he points out. “Moreover, cancers are not foreign cells, they are our own cells and are thus quite difficult to select out and target. Only by combining many disciplines of chemistry, biology (both for cancer and normal cells) and other specialized areas of expertise, can we hope to define and target highly conserved characteristics of cancer cells that are common amongst most, if not all, cancer types.”  

 

Shorr points out that at Cornerstone—where researchers discover and develop drugs that utilize or target and disrupt a highly conserved feature of cancer cells—the altered manner in which they produce and manage the energy and raw materials necessary for them to live and grow.  

 

“Our aim is to approach cancer as a singular disease in which different types can be treated in a similar fashion,” he notes. “Our integrative approach focuses on cutting edge-science and knowledge in cancer metabolism, as well as traditional small-molecule drug discovery, metabolomics, biomarker development and drug delivery, as well as traditional development technologies.”  

 

Diverse disciplines converge    

According to Dr. Ze’ev Ronai, associate director of the Sanford-Burnham Cancer Center and director of the center’s Signal Transduction Program, using multidisciplinary expertise brings together different disciplines.  

 

“Integration of science and engineering is an example,” Ronai points out. “Also, integration of molecular, cellular biology, biochemistry, pharmacology, stem cell and structural biology, proteomics, and genomics with nanomedicine offer new means for detection, monitoring and treatment of cancer.”   

 

Quite simply, Ronai notes that integrating technological and molecular disciplines “allow one to tackle problems we could not address otherwise. New means for discovery, monitoring and delivery emerge from fusing science and engineering.”  

 

The primary advantage of an integrative strategy is that tumors can be classified based on multiple criteria. 

 

“In such cases, cancers like melanoma and breast cancer can be sub-classified into several different groups. We would expect these additional groups to reflect differences in the molecular basis of each sub-class; and therefore to better inform the choice of therapy,” notes Dr. Jeffrey Smith, director of the Center on Proteolytic Pathways.  

 

Shorr points out that advantages of an integrated research approach include cross-fertilization of ideas and the integration of different perspectives that “yield new insight and avenues to be pursued that can be extremely exciting and promising.”   

 

“Yet the key issue is focus and prioritization,” he adds. “With unlimited funding and resources, we would pursue a much more integrative approach than is possible today.  Today, we need to focus on those integrative approaches that offer the greatest potential advantage.”  

 

One size does not fit all 
Whether there are forms of cancer that can be targeted more effectively through integrated research is a question that generates myriad discussion.  

 

“It is possible that those forms of cancer that are not as well understood or have had less focus in terms of research may benefit from an integrative approach that utilizes the existing knowledge from other, better understood cancers,” Shorr points out.  

 

Ronai adds that an integrated research approach can be expected to be adapted to research on all forms of cancer. It also can help thwart myriad problems, such as resistance.  

 

“Better delivery and monitoring of treatment efficacy will allow us to better refine the pool of tumor cells that require additional or different approaches for treatment and therefore will help address problems of resistance,” he says.  

 

Results stemming from an integrated approach to research also can result in innovative, less toxic therapies, he adds.  

 

“It will, as highly refined delivery techniques will result in more efficient and specific targeting, which will result in less toxic therapy,” Ronai notes.

 

“Better monitoring will assure selectivity; new approaches in drug design will help alleviate current toxicity problem commonly seen in cancer therapy.”  

 

“Since integration will lead to better sub-classification of tumors, we will be able to develop very specific therapies, and to use them only in individuals with a responsive tumor,” Smith adds. “These steps will certainly lead to drugs with a higher therapeutic index.”  

 

Making resistance futil   

Shorr points out that a goal at Cornerstone is to develop therapies that are selectively toxic to cancer cells while having minimal impact on normal cells. 

 

“By using our various areas of expertise together, we have developed two platforms that integrate classic drug discovery and development technologies with innovative and diverse technologies and science to make drugs that are more effective and safer,” he says. “These two technology platforms use two distinct, integrative approaches to cancer research and treatment.”  

 

The platforms include the Altered Energy Metabolism Directed Platform—a platform for the development of drugs that is based on a unique understanding of cancer metabolism, and in particular, mitochondrial processes involved in cancer metabolism; and the Emulsiphan Drug Delivery Platform. Emulsiphan is a novel lipid oil nanoemulsion that integrates traditional chemotherapies with this novel cancer metabolism-based drug delivery technology.  

 

Shorr points out that resistance is a significant issue for all treatment types, be they traditional chemotherapies or molecular targeted therapies.    “Cancers, like infectious diseases, tend to find a way around most, if not all therapeutics,” he explains. “This is further exacerbated in current cancer chemotherapy in that the same agents used to kill the tumors can also kill healthy cells, thus limiting the utility of these agents.” 

 

For a long time, combinations of therapies have been used to maximize the impact on cancers, just as combination therapies are used as standard of care in certain infectious diseases such as in the use of antivirals, (some of the most common examples being combination therapies for HIV and hepatitis C).

 

“It is not a stretch to imagine that the cancer treatment could resemble antiviral treatments in ongoing maintenance therapies that combine multiple, less toxic treatments designed to keep cancer at bay,” Shorr notes. “Like with antivirals, the integration of drugs that have different mechanisms of action can sometimes create additive and even synergistic effects.”  

 

Other times, as was the case with Iressa in combination with taxanes, the effect is negative. 

 

“This example, however, highlights the fact that the real understanding of combination therapies in cancer is not enough of an exact science today,” Shorr says. “A key area of need in cancer treatment involves the optimization of combinations and delivery mechanisms to get the right doses of drugs to the target (while minimizing side effects) in order to increase efficacy and overcome issues related to resistance. Addressing this problem by application of an integrated approach would offer a greater potential for identifying and developing agents that and treatment regimens that would maximize the impact on cancer cells while limiting the effects on normal healthy cells and tissues.”

 

Down with 'omics  

Proteomics, the large-scale study of proteins, particularly their structures and functions, can also offer a tool for the study of relevant samples in the context of translational cancer research. Ronai suggests that proteomics is certainly part of the toolbox required for integrative medicine, as is personal medicine.  

 

“An example of proteomics studies performed at SBMRI led to discovery of stem cells phosphoproteome,” he says. “Such analysis allow us to determine signature of protein activity, in addition to actual expression; the ability to link this information to specific tumor or response to therapy is invaluable as it allows us to reveal actual changes that take place and identify novel targets for therapy.”  

 

However, according to Shorr, the value of proteomics may be more useful in some treatment types than in others.   

 

“Is this relevant to an integrated approach? Yes, but it is only one component,” he explains. “We are focused more on metabolomics and take less from genomics, for example.  But all of these disciplines need to be taken into account for their potential value. 

 

They are all tools to be applied to the deciphering of an interdependent set of cancer-related cell activities that support cancer cell viability and reproduction.  The understanding of these many pieces of information can accelerate the development of treatments that can bring meaningful benefit to cancer patients.”  

 

Sound selection    

Perhaps the most important current focus in cancer treatment today is selecting the patients who will respond best to a particular therapy or regimen.  

 

“The idea is to not only maximize efficacy, but also to prevent patients from receiving and paying for treatments that will not benefit them or even negatively affect them,” Shorr notes. “These technologies must be integrated into the discovery and development from the period of early research. All large pharmaceutical companies require biomarkers that are linked to a drug’s mechanism of action. This will help screen for the patients most likely to respond to those therapies being developed, and may even be used to monitor drug response.”  

 

Challenges also come from the disease itself. Cancer by its nature poses challenges to researchers because, as Hollister points out, every patient’s cancer is unique to that individual.  

 

Hollister points out that there are two ways to look at cancer—the organ type and the actual molecular type of the cancer.

 

“The old way that cancer was looked at was the organ type,” she explains. “They would treat people based on the organ. For example, if the patient had colon cancer, there would be a drug treatment for that disease. As we’ve learned more about cancer and broken things down, we’ve learned that within colon cancer there are multiple segments, each with different receptors. If we can specifically treat those subsegments based on the receptor responses, we can more effectively treat the patient. The newer approach is to actually treat patient populations based on the receptors.”  

 

Efficiency and efficacy    

The integrated research approach also can save time and effort throughout the process, as evidenced by one aspect of Charles Rivers’ efforts.  

 

“The unique thing about Charles River is that we’ve spent millions and millions to create models that are tools for the pharmaceutical industry,” Hollister says. “We take potential therapies and there are hundreds that go through the screening and we have just a few, which have added value when they go to clinic because of the work we’ve done in the modeling.”  

 

The screenings also clean out many compounds that wouldn’t have been effective. As part of our mission to get effective treatment to patients more quickly, you can’t ignore the negatives that are screened out.

 

In the end, research must yield results for its ultimate measure of success. That is no different when an integrated approach is implemented. Ronai notes that there are other benchmarks for success.

 

“The development of new technologies, which were not available before, clearly bridge disciplines to result in novel means for monitoring, targeting and treatment,” he concludes. “I think the success of an integrated approach can only be measured in the improvement of survival, safety and quality of life for cancer patients. I do believe strongly that success in cancer treatment will depend on an integrated approach and likely an integrated treatment paradigm.”