If there is a Holy Grail in the drug research arena, it maybe a cure for cancer.
There are myriad companies working to develop noveltherapies to fight this insidious disease, and they are all utilizinginnovative methods to come up with potential candidates.
One method that is gaining a lot of traction in researchcircles is the integrated cancer research team. The integrated cancer researchconcept moves away from traditional academic models—which are based aroundcollaborative research in similar fields—to a team that covers a wide varietyof multidisciplinary research ideas and concepts.
In this first installment of a multi-part series in ddn, we focus on the use of integrated approaches forcancer research, with several of the industry's leading cancer authoritiesoffering a look at their own integrated approaches.
A marriage of science and medicine
It seems, though, that an integrated approach can be manythings to many people, and whether a process is an integrated approach may bein the eyes of the beholder, according to Beth Hollister, corporate vicepresident at Charles River Laboratories. She explains that an integratedapproach to cancer research marries science and medical aspects of research.
"It is a team approach that can include physicians,scientists, molecular biologists, biologists, chemists and pharmacologists, allwhom are trying get a real picture of what patients need and applying the mostadvanced scientific techniques to meet those needs," she says. "For integratedapproaches that we use at Charles River, we are taking the clinical teams andlooking three or four years ahead into cancer drug development and what iscurrently in clinical trials, where the biology is and looking at what we needto do preclinically to prepare for the next clinical trial. How we do that isto use both benchtop science, such as in vitro assays, cell-based assays andchemical-based assays, as well as animal models of cancer and apply thiscurrent 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 thosepreconceived notions.
The impression is similar for Robert Shorr, CEO ofCornerstone Pharmaceuticals, who says he views integrated approaches to cancerresearch as the convergence of a variety of often disparate disciplines andareas of expertise working together to improve cancer treatment.
"Many scientists and oncologists see cancer as manydifferent diseases, since different types of cancer originate from geneticallydiverse sources and show genotypic and phenotypic differences," he points out."Moreover, cancers are not foreign cells, they are our own cells and are thusquite difficult to select out and target. Only by combining many disciplines ofchemistry, biology (both for cancer and normal cells) and other specializedareas of expertise, can we hope to define and target highly conservedcharacteristics of cancer cells that are common amongst most, if not all,cancer types."
Shorr points out that at Cornerstone—where researchersdiscover and develop drugs that utilize or target and disrupt a highlyconserved feature of cancer cells—the altered manner in which they produce andmanage the energy and raw materials necessary for them to live and grow.
"Our aim is to approach cancer as a singular disease inwhich different types can be treated in a similar fashion," he notes. "Ourintegrative approach focuses on cutting edge-science and knowledge in cancermetabolism, as well as traditional small-molecule drug discovery, metabolomics,biomarker development and drug delivery, as well as traditional developmenttechnologies."
Diverse disciplines converge
According to Dr. Ze'ev Ronai, associate director of theSanford-Burnham Cancer Center and director of the center's Signal TransductionProgram, using multidisciplinary expertise brings together differentdisciplines.
"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, andgenomics with nanomedicine offer new means for detection, monitoring andtreatment of cancer."
Quite simply, Ronai notes that integrating technological andmolecular disciplines "allow one to tackle problems we could not addressotherwise. New means for discovery, monitoring and delivery emerge from fusingscience and engineering."
The primary advantage of an integrative strategy is thattumors can be classified based on multiple criteria.
"In such cases, cancers like melanoma and breast cancer canbe sub-classified into several different groups. We would expect theseadditional groups to reflect differences in the molecular basis of eachsub-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 researchapproach include cross-fertilization of ideas and the integration of differentperspectives that "yield new insight and avenues to be pursued that can beextremely exciting and promising."
"Yet the key issue is focus and prioritization," he adds."With unlimited funding and resources, we would pursue a much more integrativeapproach than is possible today. Today, we need to focus on those integrative approaches that offer thegreatest potential advantage."
One size does not fit all
Whether there are forms of cancer that can be targeted moreeffectively through integrated research is a question that generates myriaddiscussion.
"It is possible that those forms of cancer that are not aswell understood or have had less focus in terms of research may benefit from anintegrative approach that utilizes the existing knowledge from other, betterunderstood cancers," Shorr points out.
Ronai adds that an integrated research approach can beexpected to be adapted to research on all forms of cancer. It also can helpthwart myriad problems, such as resistance.
"Better delivery and monitoring of treatment efficacy willallow us to better refine the pool of tumor cells that require additional ordifferent approaches for treatment and therefore will help address problems ofresistance," he says.
Results stemming from an integrated approach to researchalso can result in innovative, less toxic therapies, he adds.
"It will, as highly refined delivery techniques will resultin more efficient and specific targeting, which will result in less toxictherapy," Ronai notes.
"Better monitoring will assure selectivity; newapproaches in drug design will help alleviate current toxicity problem commonlyseen in cancer therapy."
"Since integration will lead to better sub-classification oftumors, we will be able to develop very specific therapies, and to use themonly in individuals with a responsive tumor," Smith adds. "These steps willcertainly lead to drugs with a higher therapeutic index."
Making resistance futil
Shorr points out that a goal at Cornerstone is to developtherapies that are selectively toxic to cancer cells while having minimalimpact on normal cells.
"By using our various areas of expertise together, we havedeveloped two platforms that integrate classic drug discovery and developmenttechnologies with innovative and diverse technologies and science to make drugsthat are more effective and safer," he says. "These two technology platforms usetwo distinct, integrative approaches to cancer research and treatment."
The platforms include the Altered Energy Metabolism DirectedPlatform—a platform for the development of drugs that is based on a uniqueunderstanding of cancer metabolism, and in particular, mitochondrial processesinvolved in cancer metabolism; and the Emulsiphan Drug Delivery Platform.Emulsiphan is a novel lipid oil nanoemulsion that integrates traditionalchemotherapies with this novel cancer metabolism-based drug delivery technology.
Shorr points out that resistance is a significant issue forall treatment types, be they traditional chemotherapies or molecular targetedtherapies.
"Cancers, like infectious diseases, tend to find a wayaround most, if not all therapeutics," he explains. "This is furtherexacerbated in current cancer chemotherapy in that the same agents used to killthe tumors can also kill healthy cells, thus limiting the utility of theseagents."
For a long time, combinations of therapies have been used tomaximize the impact on cancers, just as combination therapies are used asstandard of care in certain infectious diseases such as in the use ofantivirals, (some of the most common examples being combination therapies forHIV and hepatitis C).
"It is not a stretch to imagine that the cancer treatmentcould resemble antiviral treatments in ongoing maintenance therapies thatcombine multiple, less toxic treatments designed to keep cancer at bay," Shorrnotes. "Like with antivirals, the integration of drugs that have differentmechanisms of action can sometimes create additive and even synergisticeffects."
Other times, as was the case with Iressa in combination withtaxanes, the effect is negative.
"This example, however, highlights the fact that the realunderstanding of combination therapies in cancer is not enough of an exactscience today," Shorr says. "A key area of need in cancer treatment involvesthe optimization of combinations and delivery mechanisms to get the right dosesof drugs to the target (while minimizing side effects) in order to increaseefficacy and overcome issues related to resistance. Addressing this problem byapplication of an integrated approach would offer a greater potential foridentifying and developing agents that and treatment regimens that wouldmaximize the impact on cancer cells while limiting the effects on normalhealthy cells and tissues."
Down with 'omics
Proteomics, the large-scale study of proteins, particularlytheir structures and functions, can also offer a tool for the study of relevantsamples in the context of translational cancer research. Ronai suggests thatproteomics is certainly part of the toolbox required for integrative medicine,as is personal medicine.
"An example of proteomics studies performed at SBMRI led todiscovery of stem cells phosphoproteome," he says. "Such analysis allow us todetermine signature of protein activity, in addition to actual expression; theability to link this information to specific tumor or response to therapy isinvaluable as it allows us to reveal actual changes that take place andidentify novel targets for therapy."
However, according to Shorr, the value of proteomics may bemore useful in some treatment types than in others.
"Is this relevant to an integrated approach? Yes, but it isonly one component," he explains. "We are focused more on metabolomics and takeless from genomics, for example. But all of these disciplines need to be taken into account for theirpotential value.
They are alltools to be applied to the deciphering of an interdependent set ofcancer-related cell activities that support cancer cell viability andreproduction. The understanding ofthese many pieces of information can accelerate the development of treatmentsthat can bring meaningful benefit to cancer patients."
Sound selection
Perhaps the most important current focus in cancer treatmenttoday is selecting the patients who will respond best to a particular therapyor regimen.
"The idea is to not only maximize efficacy, but also toprevent patients from receiving and paying for treatments that will not benefitthem or even negatively affect them," Shorr notes. "These technologies must beintegrated into the discovery and development from the period of earlyresearch. All large pharmaceutical companies require biomarkers that are linkedto a drug's mechanism of action. This will help screen for the patients mostlikely to respond to those therapies being developed, and may even be used tomonitor drug response."
Challenges also come from the disease itself. Cancer by itsnature poses challenges to researchers because, as Hollister points out, everypatient's cancer is unique to that individual.
Hollister points out that there are two ways to look atcancer—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 thepatient had colon cancer, there would be a drug treatment for that disease. Aswe've learned more about cancer and broken things down, we've learned thatwithin 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 actuallytreat patient populations based on the receptors."
Efficiency and efficacy
The integrated research approach also can save time andeffort throughout the process, as evidenced by one aspect of Charles Rivers'efforts.
"The unique thing about Charles River is that we've spentmillions and millions to create models that are tools for the pharmaceuticalindustry," Hollister says. "We take potential therapies and there are hundredsthat go through the screening and we have just a few, which have added valuewhen they go to clinic because of the work we've done in the modeling."
The screenings also clean out many compounds that wouldn'thave been effective. As part of our mission to get effective treatment topatients more quickly, you can't ignore the negatives that are screened out.
In the end, research must yield results for its ultimatemeasure of success. That is no different when an integrated approach isimplemented. Ronai notes that there are other benchmarks for success.
"Thedevelopment of new technologies, which were not available before, clearlybridge disciplines to result in novel means for monitoring, targeting andtreatment," he concludes. "I think the success of an integrated approach canonly be measured in the improvement of survival, safety and quality of life forcancer patients. I do believe strongly that success in cancer treatment willdepend on an integrated approach and likely an integrated treatment paradigm."
