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An Integrated Approach Towards The Eradication Of Her2-Driven Breast Cancer
Compelling scientific evidence suggests that HER2-overexpressing breast cancers are highly dependent on the HER2 oncogene, and these cancers can potentially be eradicated by treatments that inactivate HER2 signaling. Tyrosine kinase inhibitors (TKIs) offer this potential, but despite great successes in the highly effective treatment of Bcr-abl-driven leukemias and EGFR-driven lung cancers, HER2 has proven to be a much more resilient target for TKIs and the highly effective treatment of HER2-driven breast cancers awaits further mechanistic insight into the function of this elusive oncoprotein, and innovative approaches to inactivate it.
Our program brings together three co-PIs from the bay area across clinical and scientific disciplines in a synergistic effort to understand and overcome the barriers towards highly effective treatment of HER2-driven breast cancer. Dr. Mark Moasser is a clinician-scientist at UCSF who recently discovered that HER2-HER3 transactivation evades current TKI therapies and is considerably more difficult to suppress than previously realized. Dr. John Kuriyan is a structural biologist at the University of California Berkeley and the Howard Hughes Medical Institute who recently discovered the unique structural features underlying kinase transactivation in the HER family. His identification of the distinctive role of one kinase in the dimer as the stimulator of catalytic activity in the other has led us to the compelling hypothesis that the absence of catalytic function in HER3 is a consequence of its evolutionary selection and optimization as a stimulatory partner. Dr. Jim Wells is a cellular and molecular pharmacologist and director of the Small Molecule Discovery Center at UCSF and QB3. His pioneering work in the field of site directed drug discovery has enabled the development of a new class of drugs that act at allosteric sites, potentially interfering with intermolecular signaling functions such as HER2-HER3 transactivation.
We believe that the current evidence redefines the functionally important oncogenic target driving HER2-amplified breast cancers as the HER2-HER3 signaling complex. The challenges presented by this target are the highly evolved assignment of catalytic and stimulatory functions to specialized members in an asymmetric dimer introducing additional complexity in regulating activity, more direct access to the catalytic engine by feedback signals, and a consequent robust capacity for adaptation and perseverence. We propose an interdisciplinary program to better understand the nature of this complex target and to launch the next generation of therapeutic approaches that will finally inactivate it.
In our first aim we propose to determine the unique structural features underlying the transactivation of HER2 by HER3. We will also determine whether this stimulatory interaction is required for tumor progression in vivo. In our second aim we propose to determine the feedback signaling mechanisms that protect oncogenic HER2-HER3 transactivation against pharmacologic inhibition. We will also determine whether feedback signaling can be overcome in patients by much higher TKI dosing. This will be done in a phase I dose escalation study of lapatinib in intermittent dosing with tumor HER2-HER3 biomarker analysis. In our third aim we propose to develop a new generation of small molecule compounds that can substantially enhance our ability to disrupt HER2-HER3 transactivation. We will use innovative high throughput screening methodologies developed by the Wells group including in vitro fluorescence polarization assays, kinase transactivation assays, cell based assays, and site-directed fragment discovery approaches to identify compounds that disrupt HER2-HER3 kinase domain transactivation. Optimization of initial hits will be guided by structural information regarding their binding sites and biochemical and cell based signaling assays. Medicinal chemistry approaches may be used for optimization and candidate compounds will be tested in mouse models of HER2-driven breast cancer. Allosteric site inhibitors or HER3 binding molecules represent an entirely novel strategy based on biological evidence from the Moasser group, structural insights from the Kuriyan group and innovative methodologies from the Wells group and represent a major departure from the myriad of ATP-analog class of HER TKIs currently in development in the pharmaceutical sector. The combination of such allosteric site transactivation inhibitors with active site ATP-mimetic TKIs will likely achieve the maximal potency required to fully inactivate HER2-HER3 oncogenic signaling, and will finally reveal the true promise of the HER2 targeting treatment hypothesis.
Our project represents a significant new direction in the field by redefining the therapeutic target as the HER2-HER3 kinase dimer, with new insights into the resiliency of this oncogenic signal and a whole new generation of approaches to inactivate it. The highly HER2-dependent nature of HER2-amplified tumors suggests that drugs that can inactivate oncogenic HER2-HER3 signaling can potentially induce major tumor regressions in patients with HER2-driven breast cancers and potentially eradicate disease even in disseminated stages. This can substantially reduce and may eventually eliminate mortality from this subtype of breast cancer. We believe there now exists a critical mass of scientific information that for the first time places this idealistic goal within the foreseeable future and we propose an integrated program designed to most expeditiously deliver it.
Most cancers are driven by an extremely complex array of molecular abnormalities. However in some cancers, a single oncogene is the predominant driving force. In fact some cancers are so dependent on the function of a single oncogene that the loss of this oncogene will lead to complete regression of the cancer and disappearance of the disease. This ?Achilles Heel? scenario implies that such oncogene-dependent cancers can be cured by drugs that inactivate the driving oncogene. This principle has been successfully applied and proven in the treatment of chronic myelogenous leukemia. This type of leukemia is highly dependent on the activity of the Bcr-abl oncogene and treatment of these patients with drugs that inactivate Bcr-abl induces complete remission in almost all patients and disease eradication in many of them. This has created enormous hope that other oncogene-driven cancers can be similarly eradicated with appropriately designed drugs.
This treatment paradigm also holds true for a subset of patients with breast cancer. About 30% of breast cancers are driven by the oncogene HER2, and an overwhelming body of scientific evidence suggests that these cancers are highly dependent on HER2 and the disease cannot survive without continued HER2 function. Therefore it is a highly compelling and promising hypothesis that drugs that can inactivate HER2 will be highly effective in the treatment of this disease and can potentially eradicate this type of cancer even in advanced stages. The development of such drugs has been pursued for more than a decade. The first one, herceptin, shows some clinical activity against this disease, but it does not appear to inactivate HER2 and it may represent just the tip of the iceberg. Several tyrosine kinase inhibitors (TKIs) have now been developed to inactivate HER2 by directly inhibiting its enzymatic function. However these drugs show only limited anti-cancer activity in clinical trials. Therefore this highly promising treatment hypothesis awaits the development of much more effective HER2-targeting drugs. This forms the basis of our proposed program.
Our Promise Grant brings together three bay area co-PIs from diverse clinical and scientific disciplines who each bring to the project major recent discoveries that are highly relevant to the challenge of determining how to most effectively inactivate HER2. Dr. Mark Moasser is a physician-scientist at the University of California San Francisco who recently discovered that much of the difficulty in targeting HER2 is due its signaling partner HER3. Dr. John Kuriyan is a structural biologist at the University of California Berkeley and the Howard Hughes Medical Institute who recently discovered the mechanism by which enzymatic function in the HER family is activated and the critical role that signaling partners, such as HER3, play in the activation of kinases such as HER2. Dr. Jim Wells is a cellular and molecular pharmacologist and director of the Small Molecule Discovery Center at UCSF. He pioneered the development of drugs that can interfere with how signaling partners such as HER2 and HER3 interact and activate eachother.
The evidence our group has uncovered for the first time redefines the functionally important target driving HER2-amplified breast cancers as the HER2-HER3 complex rather than HER2 alone. The principle hypothesis behind our work is that treatments that inactivate HER2-HER3 signaling will be highly effective in the treatment of HER2-amplified breast cancer. To develop such therapies, we need to understand the unique structural and signaling characteristics that make HER2-HER3 a difficult target and to develop a new generation of drugs that act by inhibiting HER2-HER3 transactivation. We propose a program to determine the structural and signaling features that make HER2-HER3 difficult to inhibit. We will also conduct a phase I clinical trial to determine whether HER2-HER3 can be inhibited by a currently approved HER2 inhibitor at doses much higher than previously tested for HER2 alone. Using the latest and most innovative technologies for rational drug design, we propose to develop the next generation of drugs that work by inhibiting HER2-HER3 transactivation. This effort is entirely distinct from the drugs being developed in the pharmaceutical sector and this new class of drugs will eventually complement the currently developed drugs by significantly enhancing their potency.
After two decades of scientific research concerning HER2, it is now finally evident, more clearly than ever before, precisely what it will take to completely inactivate the oncogenic force underlying the HER2-positive subtype of breast cancer. We propose an integrated and multidisciplinary program to take on the challenge of developing treatments that can fully inactivate HER2-HER3 signaling. If we succeed, these efforts may, for the first time, lead to the development of highly effective treatments that could potentially eradicate disease in patients with even advanced HER2-positive breast cancer, leading to unprecedented reductions in breast cancer mortality. This seemingly surreal outcome is now within the foreseable future and we seek the support of a Susan G. Komen for the Cure Promise Grant to reach for it.