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Overcoming Resistance To A Targeted Cancer Drug

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    Overcoming Resistance To A Targeted Cancer Drug

    Scientists at Dana-Farber Cancer Institute and colleagues overseas have discovered a pair of backup circuits in cancer cells that enable the cells to dodge the effect of a widely used cancer drug. Jamming those circuits with targeted therapies may heighten or restore the drug's potency, according to a study published in Science Translational Medicine.

    The research focused on the drug cetuximab, an antibody that interferes with cancer cell growth by blocking a structure known as the epidermal growth factor receptor (EGFR). Cetuximab is effective in many patients with colorectal cancer or squamous cell cancer of the head and neck, but the benefits rarely last longer than a year, and some patients receive no benefit from the drug.

    Until now, scientists haven't known why cancers that initially respond to cetuximab become resistant to it, or how to overcome such resistance.

    In the new study, researchers led by Pasi Janne, MD, PhD, of Dana-Farber and Kimio Yonesaka, MD, PhD, formerly of Dana-Farber and now at Kinki University School of Medicine, in Osaka, Japan, found that in some cetuximab-resistant cancer cells, a protein known as ERBB2 was actively sending "grow" signals, circumventing the "stop growing" signals triggered by cetuximab. The researchers discovered that ERBB2's activity sprang from an oversupply of the protein's parent gene, Her2/neu, or by a related protein, ERBB3, when prompted by high levels of the protein heregulin. In both cases, the new growth messages are unaffected by cetuximab.

    "ERBB2 activates a critical signaling pathway that is not normally blocked by cetuximab, and in this way subverts cetuximab's function," says Janne, the study's co-senior author with Kazuhiko Nakagawa, MD, PhD, of Kinki University. "Because ERBB2 isn't affected by cetuximab, this is an easy way for cancers to become resistant to the drug."

    The findings suggest that combining cetuximab with ERBB2-inhibiting drugs could be an effective therapy for cancers that are cetuximab-resistant from the start or for those that become resistant over time, the study authors say. Several such inhibitors have already been approved, while others are undergoing clinical study.

    "We hope the findings of our study will inspire the development of clinical trials aimed at overcoming cetuximab resistance," Yonesaka remarks. "We've identified biomarkers that can be used to select cetuximab-resistant patients who may benefit from a combination of cetuximab and ERBB2 inhibitors."

    Janne estimates that up to 40 percent of colorectal cancers are cetuximab-resistant when first diagnosed. He notes that although the ERBB2 pathway may be responsible for many cases of cetuximab resistance, there are undoubtedly other pathways, yet to be discovered, that play a similar role. Further research is needed to confirm ERBB2's role in cetuximab resistance and to develop strategies for testing ERBB2 inhibitors and cetuximab in clinical trials.

    Funding for the study was provided by grants from the National Institutes of Health, the American Cancer Society, the William Randolph Hearst Foundation, and the Hazel and Samuel Bellin research fund.

    Source: Dana-Farber Cancer Institute
    Gregory D. Pawelski

    Why Resistance Develops With Targeted Cancer Drugs

    When a targeted drug is administered, perhaps it is not effective to the whole cancer cell, when trying to kill one or a few targets on or within the cancer cell? Is there something more elemental going on? Does the drug even enter the cell? Once entered, does it immediately get metabolized or pumped out, or does it accumulate?

    The cell-based functional profiling platform can provide a window on the complexity of cellular biology in real-time, gauging tumor cell response to chemotherapies (conventional and targeted). By examining drug induced cell-death, functional analyses measure the cumulative result of all of a cell's mechanisms of resistance and response acting in concert. Functional profiling approximates the cancer of the "individual" not populations.

    In photomicrographs of cell-based assays, it is fairly easy to see that some clones of tumor cells don't accumulate a drug. These cells won't get killed by it. But you wouldn't pick this up with an assay which only measured the mechanism (pathway) themselves. The functional profiling platform measures the net effect of everything which goes on (whole cell profiling). Are the cells ultimately killed, or aren't they?

    There is really no right mutation or wrong mutation. There are the right drugs and the wrong drugs. There are "sensitive" drugs and there are "resistant" drugs. Patients would certainly have a better chance of success had their cancer been "chemo-sensitive" rather than "chemo-resistant" where it is more apparent that chemotherapy improves the survival of patients, and where identifying the most effective chemotherapy would be more likely to improve survival.

    For example, Sutent is one of tne of the new "multi-targeted" drugs. In the assay, it is conveniently pigmented brilliant yellow. Easy to see which cells have taken it up. In the attached photomicrographs (two magnifications), it is fairly easy to see that some clones of tumor cells don't accumulate the drug. These cells won't get killed by it. The assay measures the net effect of everything which goes on. The integrated effect of the drugs on the whole cell, resulting in a cellular response to the drug, measuring the interaction of the entire genome.

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    Source: Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S (June 20 Supplement), 2006: 17117
    Gregory D. Pawelski


      Research in Combining Targeted Agents Faces Numerous Challenges

      By Margot J. Fromer
      ASCO Post
      September 1, 2011, Volume 2, Issue 13

      If the clinical trials endeavor in oncology is falling short of its goals and if targeted agents have not kept their promise, can a new approach to drug development provide a solution?

      Very possibly, said John Hohneker, MD, Chair of the Workshop Planning Committee for the conference, “Facilitating Collaborations to Develop Combination Investigational Cancer Therapies,” held in Washington in mid-June and sponsored by the Institute of Medicine (IOM) National Cancer Policy Forum. He is also Senior Vice President and Global Head of Development, Integrated Hospital Care, Novartis.

      Dr. Hohneker said that the purpose of the workshop was to talk about the many barriers to this new approach to cancer treatment. “Combining investigational products early in their development is thought to be a promising strategy, especially when they target multiple pathways (or more than one step in a pathway), thus conferring greater benefit than therapy directed at a single target.”

      Unfulfilled Promise

      Jane Perlmutter, PhD, founder of the Gemini Group, a consulting company, added, “The problem with the way cancer research is conducted is that the biology of the disease is so complicated that, although technology keeps advancing, personalized medicine is still mostly only a promise.”

      Targeted agents for cancer haven’t panned out to the extent hoped. Although a few might work sometimes or for a short time, the effects have not been significant or durable. And many are more toxic than expected. “Their regulation is confusing and/or interpreted too conservatively, and despite the great need, there is limited incentive for pharmaceutical companies to collaborate with each other,” said Dr. Perlmutter.

      Advances in genomics and cell biology have paved the way for increasingly sophisticated targeted therapies, but cellular pathways contain redundancies that can be activated in response to inhibition of one or another pathway, thus promoting emergence of resistant cells and clinical relapse.

      The traditional path to drug development, even targeted therapy, has been one at a time. Sometimes a new drug is added to a standard regimen and then compared to the standard alone, but regardless of how or with what it is used, it has to work on its own.

      Cooperative Development

      This system is no longer completely viable in cancer and needs to be modernized. A new approach would provide the flexibility to evaluate combination regimens in a single development program that can screen all tumors for their pathway dependencies, resulting in efficacy based on screening results and experience with patterns of resistance.

      However, despite the potential benefits of such a scheme, uncertainty and risk abound. First, it is usually impossible to characterize the effects of the individual components. Second, combinations would probably yield considerably less information about safety and efficacy than would have been available had they been developed individually. Third, patients and physicians must not only be informed of more-than-usual risk, they must be willing to accept it. Fourth, there should be a compelling biologic rationale for their use and substantial reasons why the agents cannot be developed individually.

      The Science Is Complex

      James Doroshow, MD, Deputy Director for Clinical and Translational Research, NCI, discussed the scientific challenges facing development of combination targeted therapeutics:

      The mechanisms of action for a growing number of targeted agents that are available for trials are not completely understood.

      Lack of the right assays or imaging tools means inability to assess the target effect of many agents, and assays are not standardized.

      Preclinical models to evaluate efficacy, dosing schedule effects, biomarker utility, and toxicity are not available for combination therapies.

      Clinical trials methodology remains unclear with regard to numbers of patients, tumor biopsies, relevance of histologic homogeneity, and pharmacokinetic interactions.

      Intellectual property and regulatory matters are daunting.

      Dr. Doroshow also discussed mechanism of action (or mechanism of resistance) studies in early-phase trials. Problems include the evaluation of actual vs presumed sites of target engagement, evidence to support further development, demonstration of the relationship between dosing schedule and systemic exposure to target effects, and relevance of biomarkers.

      “In addition, we need to investigate the molecular effects, toxicology, and other safety signals of combination agents in surrogate tissues,” said Dr. Doroshow. “This is a huge undertaking, and unfortunately it is not necessarily predictive of clinical benefit. That requires larger, later-stage trials.”

      Michael T. Barrett, PhD, Associate Professor and Head of the Oncogenomics Laboratory, TGen, added that cancer is extremely genetically unstable, resulting in highly karyotypically and biologically individual malignancies. Thus, each patient’s cancer could require its own specific therapy. Even if this were possible and practical, the treatment could ultimately be thwarted by emergence of a resistant variant genetic subline.

      Dr. Barrett also noted that each genome has unique sets of selected aberrations and mutations, of which multiple populations can be present at biopsy. These mutations can be asymmetric; they can progress and metastasize, and thus resist treatment. He warned that application of genomic tools to combination therapy has to be based on unbiased profiling of biopsies, as well as identification of therapeutic vulnerabilities in all patients.

      Kurt Bachman, PhD, Head of Translational Medicine and Biology, GlaxoSmithKline, added, “The challenge is to identify the tumor types most likely to respond, to find biomarkers that predict a response, and to define the relationship of the predictors to the biology of the inhibitors.”

      Disclosure: Dr. Hohneker is employed by and owns stock in Novartis. Dr. Barrett has a current research contract with AstraZeneca. Dr. Bachman is employed by GlaxoSmithKline. Dr. Perlmutter reported no potential conflicts of interest. Dr. Doroshow reported no potential conflicts of interest.
      Gregory D. Pawelski


        Targeted Therapies for Cancer Confronts Hurdles

        In a conference sponsored by the Institute of Medicine, scientists representing both public and private institutions examined the obstacles that confront researchers in their efforts to develop effective combinations of targeted cancer agents.

        In a periodical published by the American Society of Clinical Oncology (ASCO) in their September 1, 2011 issue of the ASCO Post, contributor Margo J. Fromer, who participated in the conference, wrote about it.

        One of the participants, Jane Perlmutter, PhD, of the Gemini Group, pointed out that advances in genomics have provided sophisticated target therapies, but noted, “cellular pathways contain redundancies that can be activated in response to inhibition of one or another pathway, thus promoting emergence of resistant cells and clinical relapse.”

        James Doroshow, MD, deputy director for clinical and translational research at the NCI, said, “the mechanism of actions for a growing number of targeted agents that are available for trials, are not completely understood.”

        He went on to say that the “lack of the right assays or imaging tools means inability to assess the target effect of many agents.” He added that “we need to investigate the molecular effects . . . in surrogate tissues,” and concluded “this is a huge undertaking.”

        Michael T. Barrett, PhD, of TGen, pointed out that “each patient’s cancer could require it’s own specific therapy.” This was followed by Kurt Bachman of GlaxoSmithKline, who opined, “the challenge is to identify the tumor types most likely to respond, to find biomarkers that predict response, and to define the relationship of the predictors to biology of the inhibitors.”

        What they were describing was precisely the work that clinical oncologists involved with cell culture assays have been doing for the past two decades. One of those clinicians, Dr. Robert Nagourney felt that there had been an epiphany.

        The complexities and redundancies of human tumor biology had finally dawned on these investigators, who had previously clung unwaiveringly to their analyte-based molecular platforms.

        The molecular biologists humbled by the manifest complexity of human tumor biology had finally recognized that they were outgunned and whole-cell experimental models had gained the hegemony they so rightly deserved.

        Source: Dr. Robert A. Nagourney, medical director, Rational Therapeutics and instructor in Pharmacology at the University of California, Irvine School of Medicine.
        Gregory D. Pawelski