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From Shotgun to Gatling Gun: Multibarreled Approach to Cancer Treatment

Keller, Daniel M. PHD

doi: 10.1097/01.COT.0000352164.72874.56

As the number of new, targeted anti-cancer drugs increases, a consensus is forming that except in rare cases, what is needed is not a single targeted rifle shot for any one specific cancer, bur rather a “Gatling gun”* of multiple barrels aimed at interrelated targets.



At the most recent Molecular Targets in Cancer Therapeutics Symposium of the European Organisation for Research and Treatment of Cancer (EORTC), National Cancer Institute, and American Association for Cancer Research, and again at the San Antonio Breast Cancer Symposium, several leading researchers stressed to OT the need to target multiple pathways or multiple points within a pathway at the same time to control cancer.

These experts said that single targeted agents will have only modest activity alone. It is still too early to predict which specific combinations of targeted therapies may turn out to be best. But oncologists are becoming comfortable with the concept of using multiple targeted agents such as monoclonal antibodies and tyrosine kinase inhibitors (TKIs) without chemotherapy.

Nonetheless, it appears that chemotherapy is here to stay for a long time, and new combinations of novel agents will require vigilance for unexpected toxicities.

“We are learning that some of the simplistic views of biological therapy or targeted therapy are totally unwarranted and that some of these combinations will be more toxic than we expect,” said Gabriel Hortobagyi, MD, Professor and Chairman of the Department of Breast Medical Oncology at the University of Texas M. D. Anderson Cancer Center. He cited recent reports of high toxicity with a combination of bevacizumab and sunitinib as an example.

Dr. Hortobagyi said that ample preclinical evidence suggests that interrupting a pathway at multiple levels can be beneficial—for example, combining trastuzumab and pertuzumab (a monoclonal antibody that inhibits dimerization of HER2 with itself or other HER receptors) or using trastuzumab or lapatinib with downstream effectors such as additional TKIs for HER2-positive breast cancer.

“Ultimately, it still depends on careful and critical clinical validation,” he advised.

Brian Leyland-Jones, MD, PhD, Director of the Winship Cancer Institute at Emory University in Atlanta, concurred that one agent is almost certainly going to be insufficient: “The question is how many of these pathways do you need to block?,” and he predicted that tumor gene maps could direct targeted therapies. He, like others, also acknowledged the looming issue of affordability of using multiple novel agents.

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Is ‘Dirtier’ Better?

Single, very targeted drugs have shown great efficacy in a few specific cases—e.g., imatinib for chronic myelogenous leukemia and gastrointestinal stromal tumors. “But there are also good examples for the other philosophy, for the more dirty drugs, the multi-targeted agents, the sunitinibs, the sorafenibs,” said Patrick Schöffski, MD, MPH, of the Department of General Medical Oncology at Catholic University in Leuven, Belgium.

As Chairman of the EORTC Scientific Committee, he said he sensed from the meeting that opinions were moving toward using drugs with a broader activity profile as opposed to combining multiple, very specific agents.

“The problem with the latter strategy is that we are still lacking adequate methodology for it,” he said. “Almost none of us have experience with combining targeted agents, non-approved drugs in the IND or pre-IND phase with each other in Phase I.” He predicted that Phase I data on combinations of first-in-class kinds of drugs will be forthcoming at the next two annual EORTC-NCI-AACR conferences.

One strategy, so-called vertical blockade, is to inhibit a single pathway at multiple points, such as at a cell surface receptor and its downstream intracellular signaling molecules. One example testing such a strategy is the Adjuvant Lapatinib and/ or Trastuzumab Treatment Optimisation (ALTTO) trial in HER2-positive breast cancer to evaluate outcomes with lapatinib or trastuzumab alone, sequentially, or in combination.

Whereas trastuzumab blocks the HER2 cell surface receptor, lapatinib acts “vertically” downstream to inhibit the tyrosine kinase associated with HER2 (as well as the TK of the epidermal growth factor receptor [EGFR]).

On the other hand, Stephen Johnston, MD, PhD, Consultant Medical Oncologist at the Royal Marsden Hospital, described horizontal blockade as “where you've got several pathways all working together,” and each is blocked individually—“The real challenge moving forward will be to partner the signaling agents together in a smart way, managing unpredictable toxicity, and then blocking the relevant pathways, either horizontally or vertically. And that's really where the field is moving now,” he said.



In the view of Lucio Miele, MD, PhD, Professor of Pathology and Pharmacology and Associate Director for Translational Science at the Cardinal Bernardin Cancer Center of Loyola University, the signaling system in cells, including tumor cells, is so interconnected that simply hitting one target causes the system to reset itself and go to another status that is capable of surviving.

“So it's extremely difficult in practice to completely eradicate a large population of tumors with a single agent without either causing resistance through genetic mutations or simply triggering adaptation that may be epigenetic…. So, absolutely, combinations must be the name of the game,” he said.

Even though in vitro and preclinical models do not always translate into success in the clinical setting, they can inform the selection of drug combinations for clinical trials. Joseph Tomaszewski, MD, Deputy Director of the NCI's Division of Cancer Treatment and Diagnosis, said the Developmental Therapeutics Program in his division has created a “combo plate” to test newer agents more efficiently: “So you'd be able to do combination studies in a relatively facile fashion.”

The endeavor started early last year, and he predicted that the first results should start to appear in the next few months.

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Targeting Processes, Not Just Molecules

In his McGuire lecture at the San Antonio Breast Cancer Symposium, Larry Norton, MD, Deputy Physician-in-Chief for Breast Cancer Programs at Memorial Sloan-Kettering Cancer Center, talked about the “tool kit that cancers need to cause disease.” These tools are cell mobility, tissue invasiveness, and the ability to establish a tumor in a foreign niche (tissue) through blood vessel and stromal formation.



Cell replication is in that picture, he said, but may actually be secondary to these other biological events.

“The important point here is that we are now developing agents for the first time that attack many steps of the cancer process, not just mitosis, which has dominated our thinking for many, many years,” Dr. Norton said.

“So now we're able to incorporate anti-mitotic therapy with anti-angiogenic therapy and perhaps even anti-mobility therapy. As an example, the taxanes, by disrupting microtubules, block mitosis and also interfere with cell mobility.”

While matrix metalloproteinase inhibitors have not proven very useful as single agents, Dr. Norton said that they may synergize with agents that attack other aspects of malignancy. “So the multi-pronged attack on cancer by attacking more than just the level of regulation of mitosis I think has enormous promise,” he said.

Particularly promising may be multifunctional drugs, such as the immunoconjugate T-DM1 that is in development. Here, trastuzumab is conjugated with a maytansine derivative, which is released inside of a cell bearing the HER2 receptor. Dr. Norton said it could act similarly to trastuzumab on HER2 while delivering the anti-mitotic, and possibly anti-motility, maytansine derivative to the cell as well.

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To See It Doesn't Mean to Treat It

Just because a molecular marker appears on a tumor does not mean that it is a good therapeutic target, even if it is a valid prognostic marker. “That's making an assumption that everybody is making, but I think it's dangerous,” said Jaap Verweij, MD, PhD, Chair of the Department of Medical Oncology at Erasmus University Medical Center in Rotterdam, Netherlands.

Speaking with OT at the EORTC-NCI-AACR conference, he gave the example of the EGFR in non-small cell lung cancer. While it may be prognostic for survival (a controversial point in itself), “That doesn't mean it's a predictive marker for the outcome of effect of EGFR inhibition,” he said. “So we have to discriminate predictive markers for treatment outcome from prognostic markers.”

Based on “all the failures that we've had with many of those markers that we chased,” he urged caution in designing therapies merely based on the presence of certain molecular markers on tumor cells.



Mark Pegram, MD, Professor of Medicine and Director of the Translational Research Program at the Braman Breast Cancer Research Institute of the University of Miami Miller School of Medicine, echoed Dr. Hortobagyi's sentiment that the proof of clinical utility will come only from clinical trials.

For example, reports of EGFR-mediated upregulation of vascular endothelial growth factor (VEGF) in colon cancer cells suggested that combinations of anti-EGFR antibodies plus bevacizumab might show greater efficacy than either alone. Although Phase II clinical data looked, in two Phase III trials of different anti-EGFR antibodies, there was no significant benefit of adding bevacizumab to chemotherapy and the antibodies, and there was possibly a trend toward worse outcomes, Dr. Pegram noted.

“So it's a word of caution…. Certainly we need randomized Phase III studies before we start thinking about integrating any of these combinations into routine clinical practice.”

He said he hopes trials of bevacizumab plus trastuzumab will give better results in the setting of HER2- positive breast cancer, in which HER2 is markedly upregulated compared with the levels of EGFR seen on colon cancer cells.

Dr. Miele expressed in general “that the right combinations will depend on the indication and even subsets of patients within a given indication.”

One can not assume that if a combination works in one model or tumor type, it will work in another setting: “All of these pathways have effects that are greatly context dependent—meaning that in different cells or in the presence of different stimuli, you may find different effects,” Dr. Miele concluded.

*Editor: Note to those, like me, who had not heard of this before, from Wikipedia: “The Gatling gun (1861) was one of the most well-known rapid-fire weapons to be used in the 1860s by the Union forces of the Civil War…. Although the first Gatling gun was capable of firing continuously, it required human power to crank it; as such it was not a true automatic weapon. Each barrel fired a single shot as it reached a certain point in the cycle after which it ejected the spent cartridge, loaded a new round, and in the process, cooled down somewhat. This configuration allowed higher rates of fire without the problem of an overheating single barrel. The original Gatling gun was designed by the American inventor Dr. Richard J. Gatling in 1861, who wrote that he made it to reduce the size of armies and so reduce the number of deaths by combat and disease.”
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