Dennis Slamon, MD, PhD, and Carlos L. Arteaga, MD, discuss recent advances in anti-HER2 targeted therapies and the role of signaling by oncogenes.
Dennis Slamon, MD, PhD
Director, Clinical/Translational Research Director, Revlon/UCLA Women’s Cancer Research Program Chief, Division of Hematology/Oncology Jonsson Comprehensive Cancer Center University of California, Los Angeles
Carlos L. Arteaga, MD
Director, Breast Cancer Research Program Associate Director, Clinical Research Professor of Medicine and Cancer Biology Vanderbilt-Ingram Cancer Center Nashville, TN
Dennis Slamon, MD, PhD, played a leading role in the research that resulted in the development of Herceptin in the 1990s and remains involved in research into targeted therapies. Carlos L. Arteaga, MD, focuses on the role of signaling by oncogenes in the progression of breast tumor cells and molecular therapies in breast cancer. They discussed recent advances in separate interviews with OncologyLive.
Slamon: In normal cells, human epidermal growth factor receptor 2 [HER2] is a critical member of the HER receptor family that is involved in proliferation, differentiation, motility, and programmed cell death, all critical functions for normal cells. In malignancy, the gene is altered by amplification in about 20% to 25% of human breast cancers and a smaller percentage of other human cancers. When amplified, the expression of HER2 goes way beyond its normal dynamic range—there is a wide range of normal HER2 expression—so that you get pathologic overexpression. When overexpressed to this extent, it plays a dominant role in proliferation and motility and resistance to hormonal control.
Slamon: Clearly, homodimerization and heterodimerization are the most effective forms of signaling that the HER family executes, and when the gene is amplified in cancer it is probably still working through dimerization partners, so it plays an important role.
Arteaga: HER2 dimerization (both ligand-dependent and ligand-independent), particularly HER2-HER3 dimer formation, is the main mechanism of signaling through HER2. HER2-HER3 dimerization is a particularly important aspect of HER2 signaling as these dimers potently signal to the phosphatidylinositol-3-kinase (PI3K) survival pathway and are the main mechanism driving HER2-positive cancers.
Slamon: All of the antibodies directed against the HER2 extracellular domain (ED) play a potential role in inhibiting dimerization. The two that are currently out there are the approved drug trastuzumab and the experimental drug pertuzumab, which bind to different regions on the ED. Each of them plays a role in inhibiting the dimerization phenomena.
As single agents, the most effective is trastuzumab. When we compared trastuzumab activity preclinically, we looked at all the drugs, including pertuzumab (which used to be called 2C4 when I worked on it), and the best antibody for inhibiting HER2 growth in vivo and in vitro was the drug that became trastuzumab, and pertuzumab was maybe the second or third best.
But when you hit the receptor twice, it appears you have even better activity. We had preclinical data from our lab from several years ago that demonstrated this, and we also had data that showed that lapatinib plus trastuzumab was also better than either agent alone. So, it appears that two assaults on the receptor gives you synergistic activity.
Arteaga: These are drugs or molecules that disrupt the association or coupling of HER2 to other receptors such as epidermal growth factor receptor (EGFR) and HER3. These would include trastuzumab, pertuzumab, and HER3 antibodies.
Overall, these represent an important class of agents as they disrupt a central mechanism of signaling by the HER2 receptor. In addition to trastuzumab and pertuzumab, there are two HER3 antibodies in clinical development that disrupt heregulin (HER3 ligand)-induced HER2-HER3 dimerization: MM-121 from Merrimack and U3-1287 from U3 Pharma and Daiichi-Sankyo.
At the 2011 San Antonio Breast Cancer Symposium, Novartis presented an exciting novel HER3 antibody that blocks both ligand-dependent and ligand-independent formation of HER2-HER3 dimers. Preclinical data suggested this monoclonal antibody could be mechanistically superior to the other two HER3 antibodies, but it has not been tested in patients yet.
Slamon: In preclinical testing, we saw evidence of synergy with dual inhibition, which we published in 2006. We talked about doing clinical trials at the time, but there was not a lot of enthusiasm. Data have now come in in both NeoALTTO and CLEOPATRA that combinations, either with the tyrosine kinase inhibitor or with the antibody, are better than a single hit on the receptor.
Arteaga: HER2 dimer formation can be ligand-induced or ligand-independent. Trastuzumab blocks the latter and pertuzumab blocks the former type of dimers. Together, these drugs have synergistic activity against HER2- positive cancer cells by completing the inhibition of both types of HER2 signaling dimers.
One cannot rule out the potential contribution of antibody-dependent, cell-mediated cytotoxicity (ADCC), as both antibodies can mediate that cellular response. Conceptually, this dual strategy could be applied to EGFR-driven tumors, for example, by combining cetuximab or panitumumab with HER2 or HER3 antibodies.
In principle, pertuzumab should also block EGFR-HER2 dimers. EGFR antibodies that block dimerization of EGFR with other receptors have not been reported to my knowledge. There is a recent report in Cancer Cell from 2011 of a bifunctional antibody made by Genentech that simultaneously binds to and blocks both EGFR and HER3. There are other approaches to a dual blockade (ie, a combination of trastuzumab plus lapatinib used in NeoALTTO). Another “dual” approach in early clinical development could be trastuzumab plus a PI3K inhibitor. In that case, the “dual” approach targets different molecules or nodes in the HER2 pathway, the HER2 receptor, and PI3K immediately downstream.
Slamon: I think it’s a more comprehensive blockade on HER2 signaling. A lot of people have argued that it’s a result of increased antibody-dependent cell-mediated cytotoxicity, but then the NeoALTTO results wouldn’t make a whole lot of sense, so I think it is profoundly a result of the impact on signaling.
Arteaga: In the case of CLEOPATRA, it is easy to propose that the improved clinical benefit is due to a more comprehensive blockade of HER2 signaling. Frankly, I think these results were expected and, as strongly suggested by the mechanistic and preclinical data, the results could almost have been written before the trial.
Slamon: Well, I think it’s just now beginning to be explored, but I think the results are real and these combinations will be used in the future. The question is how will other combinations fare against this combination, meaning combined blockade of the HER pathway and then parallel pathways like PI3K, or angiogenic pathways, or some of the other things that are being looked at. These are all being evaluated in clinical trials, which I think is very exciting. Combination strategies are clearly going to be something we’ll be evaluating and very likely using in the near future.