Treatment Of HER2-positive Cancer Research Articles

The Role of Tumor-Associated Antigen HER2/neu in Tumor Development and the Different Approaches for Using It in Treatment: Many Choices and Future Directions.

The treatment of HER2-positive cancers has changed significantly over the past ten years thanks to a significant number of promising new approaches that have been added to our arsenal in the fight against cancer, including monoclonal antibodies, inhibitors of tyrosine kinase, antibody-drug conjugates, vaccination, and particularly, adoptive-T-cell therapy after its great success in hematological malignancies. Equally important is the new methodology for determining patients eligible for targeted HER2 therapy, which has doubled the number of patients who can benefit from these treatments. However, despite the initial enthusiasm, there are still several problems in this field represented by drug resistance and tumor recurrence that require the further development of new more efficient drugs. In this review, we discuss various approaches for targeting the HER2 molecule in cancer treatment, highlighting their benefits and drawbacks, along with the different mechanisms responsible for resistance to HER2-targeted therapies and how to overcome them.

The Nrf2 inhibitor brusatol synergistically enhances the cytotoxic effect of lapatinib in HER2-positive cancers

The dual tyrosine kinase (EGFR/HER2) inhibitor lapatinib is currently used to clinically treat HER2-positive breast cancer. However, a majority of patients do not respond to lapatinib therapy within 6 months. Therefore, potentiating the anti-tumor effect of lapatinib by combination treatment has a great potential to overcome the obstacle. Herein, we aim to investigate the anti-tumor activity of lapatinib in combination with brusatol and explore the potential mechanism involved in the combinatorial treatment. Our findings revealed that the Nrf2 inhibitor brusatol potently enhanced the anti-tumor effect of lapatinib against SK-BR-3, SK-OV-3 and AU565 cancer cells in a synergistic manner. Furthermore, we found that lapatinib plus brusatol more effectively decreased Nrf2 level and induced ROS generation in both SK-BR-3 and SK-OV-3 cells. Moreover, we also observed a significant reduction on the phosphorylation of HER2, EGFR, AKT and ERK1/2 in SK-BR-3 and SK-OV-3 cells when treated with lapatinib plus brusatol compared to either agent alone. More importantly, brusatol significantly augmented the anti-tumor effects of lapatinib in the SK-OV-3 xenograft model. In summary, these data provide a potential rationale for the combination of brusatol and lapatinib on the treatment of HER2-positive cancers.

Abstract LB170: HER2-targeted interferon-beta-1a mutein, a potent immunocytokine for the treatment of HER2-positive cancers

Abstract Background: Interferon beta (IFN-β), a promising potent cytokine, has been attracting attention for treatment of cancer. The pleiotropic antitumor effects of IFN-β have been studied, with specific reference to their direct role on cancer cells and indirect action through the immune effector cells. However, its systemic toxicities and poor biophysical properties prevent IFN-β from being widely used for cancer therapy. Since the potential of cytokine therapies are impaired due to dose-limiting systemic toxicities, novel treatment methods should be developed to safely deliver effective drug quantities at the tumor sites. Like antibody-drug conjugates (ADCs), immunocytokine can be attempted to induce cytokine's organ-targeting and alleviate its systemic side effects. Here, we designed recombinant IFN-β mutein immunocytokines that comprise a HER2-targeting antibody and IFN-β mutein, and evaluate the antitumor properties against HER2-positive cancers.Method: A panel of human gastric cancer cell lines was treated with trastuzumab-IFN-β mutein to evaluate direct antitumor effect. In addition, to test the immune cell-mediated antitumor effect, cancer cells were co-cultured with effector cells (e.g. PBMC) in the absence or drug. The antitumor efficacy of trastuzumab-IFN-β mutein in vivo was tested in HER2-positive cancer xenograft models using nude mice or humanized mice. Result: Trastuzumab-IFN-β mutein directly inhibited the growth of HER2-positive gastric cancer cell lines and was more effective than trastuzumab or IFN-β mutein alone. Trastuzumab-IFN-β mutein also displayed enhanced immune cell-mediated cytotoxicity. Collectively, trastuzumab-IFN-β mutein may have indirect immune cell-mediated antitumor effects and direct cell growth inhibitory effects. Moreover, trastuzumab-IFN-β mutein significantly suppress tumor growth in HER2-positive cancer xenograft models. Tumor-infiltration of lymphocytes was enhanced by trastuzumab-IFN-β mutein, implying that the tumor-targeting IFN-β may have an antitumor effect through increased immune response. Conclusion: We have characterized and evaluated the antitumor properties of trastuzumab-IFN-β mutein in HER2-expressing cancers. Since IFN-β activates antitumor immune responses, it is expected to be administered in combination with immunotherapeutic drugs. Therefore, the study suggests that trastuzumab-IFN-β mutein is a promising candidate for the treatment of HER2-positive carcinoma. Citation Format: Chan Gyu Lee, Tae Eun Kim, Sungyoul Hong, Jongwan Chu, Ju Eun Kang, Hae Min Jeong, Young Kee Shin. HER2-targeted interferon-beta-1a mutein, a potent immunocytokine for the treatment of HER2-positive cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB170.

Virus-like particle display of HER2 induces potent anti-cancer responses

ABSTRACTOverexpression of human epidermal growth factor receptor-2 (HER2) occurs in 20–30% of invasive breast cancers. Monoclonal antibody therapy is effective in treating HER2-driven mammary carcinomas, but its utility is limited by high costs, side effects and development of resistance. Active vaccination may represent a safer, more effective and cheaper alternative, although the induction of strong and durable autoantibody responses is hampered by immune-tolerogenic mechanisms. Using a novel virus-like particle (VLP) based vaccine platform we show that directional, high-density display of human HER2 on the surface of VLPs, allows induction of therapeutically potent anti-HER2 autoantibody responses. Prophylactic vaccination reduced spontaneous development of mammary carcinomas by 50%-100% in human HER2 transgenic mice and inhibited the growth of HER2-positive tumors implanted in wild-type mice. The HER2-VLP vaccine shows promise as a new cost-effective modality for prevention and treatment of HER2-positive cancer. The VLP platform may represent an effective tool for development of vaccines against other non-communicable diseases.

Abstract P2-05-25: TIMP-4 expression correlates with disease progression among HER2-positive breast cancers

Abstract Breast cancer with HER2 gene amplification accounts for 20-25% of invasive breast cancer. HER2 activates the PI3K/Akt and MAPK pathways promoting survival and cell proliferation resulting in aggressive biological behavior and poorer prognosis for the patient. Although trastuzumab (Herceptin®), a recombinant humanized antibody, offers effective treatment of HER2-positive cancers, a proportion of patients will not respond to trastuzumab-based regimens and those who do respond can lose clinical benefit during the late stages of their treatment. In this IRB-approved study we have assessed HER2 and LuminalB subtypes of invasive breast cancer from an archival collection together with specimens collected in an on-going prospective study for the expression of tissue inhibitor of metalloproteinase-4 (TIMP-4), an inducer of the PI3K/Akt pathway and its possible correlation to trastuzumab resistance. Circulating TIMP-4 in the stroma binds to CD63 on the tumor epithelial cells and initiates a signaling cascade through interaction with β1-integrin. We have previously demonstrated that elevated levels of TIMP-4 confers poor survival prognosis for triple-negative breast cancers. Genomics data found at TCGA, cBioPortal for Cancer Genomics1 have showed that TIMP-4 is amplified in 24% of breast cancer patients. Therefore, we propose that the reported ˜20% of HER2-positive patients that will not respond to trastuzumab could in fact be TIMP-4 positive and have active PI3K/Akt signaling. In this on-going study, we have to date examined twenty-nine patients with HER2 gene amplification. Among these, eight had elevated levels of TIMP-4 as determined by immunohistochemistry, and seven had progression of their disease within one year of starting systemic therapy (all with metastasis to brain) while one had local recurrence 5 years after starting therapy. Two of these patients had stage IA disease, one had IIA, three had IIB and two were diagnosed with stage IIIC disease. These results suggest that TIMP-4 amplification could be, at least in part, responsible for the trastuzumab resistance due to TIMP4's ability to promote survival and cell proliferation by a continuous activation of the PI3K/Akt pathway. In an attempt to test if a monoclonal antibody specific for human TIMP-4 could be used to prevent or alleviate the trastuzumab resistance, we are using human breast cancer cell-lines with amplified HER2, with and without CD63 expression as well as a CD63 knock-out line. From these experiments we hope to learn if treating for TIMP-4 could be an approach for future clinical intervention for the patients that have HER2 gene amplification and elevated levels of TIMP-4. 1 Gao et al. Sci Signal. 2013 and Cermi et al . Cancer Discov. 2012. Citation Format: Isaac KM, Zemba-Palko V, Sabol JL, Blair L, Behbod F, Wallon UM. TIMP-4 expression correlates with disease progression among HER2-positive breast cancers. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-05-25.

Treatment of HER2-positive metastatic breast cancer.

Treatment of HER2-positive metastatic breast cancer.

139 GBR1302: a BEAT® bispecific antibody for the treatment of HER2 positive cancers

139 GBR1302: a BEAT® bispecific antibody for the treatment of HER2 positive cancers

Abstract 5442: Biodistribution and antitumor efficacy study of novel Her2 targeting DARPins

Abstract Introduction: DARPins are genetically engineered small-sized proteins exhibiting high affinity for target proteins. The epithelial growth factor receptor 2 (Her2/neu) is a target of interest for targeted therapies as it is overexpressed in epithelial tumors such as breast and gastric cancers. Antitumor activity and biodistribution of novel Her2-targeting DARPins were evaluated in mice bearing Her2-positive human breast tumors. Materials and methods: Antitumor activity and biodistribution studies were performed in female Balb/c Nude mice bearing subcutaneous BT-474 human breast tumors. Mice were treated intravenously (IV) every 3 days with five different DARPins at 20 or 35 mg/kg and antitumor activity was evaluated by measuring tumor growth twice weekly. For the biodistribution study, DARPins were radiolabelled with technetium-99m (99mTc) using the IsoLink procedure. Quality control of the radiolabelled DARPins was performed by size exclusion chromatography, ELISA assay, and binding to tumor cells. 99mTc-radiolabelled DARPins were injected IV to mice at 23-25 MBq/mouse. 4 and 24 hours post-injection, animals were euthanized for blood, tumor and organ collection. Radioactivity in each sample was measured and normalized to sample weight and injected dose (% ID/g). The depth of tumor penetration of 99mTc-radiolabelled DARPins was also assessed by planar autoradiography imaging. Results: All five DARPins displayed a significant antitumor activity. Four DARPins induced BT-474 tumor regression while the fifth led to BT-474 tumor stasis. All DARPins were efficiently radiolabelled with 99mTc to radiochemical purities within 50% to 90%, and they all retained the ability to fully bind Her2. The five DARPins displayed a comparable distribution pattern. Radioactivity uptake in blood ranged from 25-30% and 8-10 % ID/g at 4 and 24 hours post-injection, respectively. Accumulation in tumors increased from 6-10% ID/g at 4 hours to 12-20% ID/g at 24 hours. All 99mTc-radiolabelled DARPins were excreted through the liver and kidneys and radioactivity uptake in both organs, respectively, ranged from 7-14% ID/g and 4-8% ID/g at 24 hours post-injection. Planar autoradiography imaging revealed that the depth of penetration of DARPinsinto the tumor was > 2 mm as soon as 4 hours post-injection. Conclusions:The five anti-Her2 DARPins investigated efficiently targeted BT-474 tumors and significantly inhibited their growth, making them attractive as new therapeutic agents for the treatment of Her2-positive cancers. Their easy radiolabelling with 99mTc also makes them attractive tools for imaging with diagnostic and predictive purposes, for instance to follow the modulation of Her2 expression during therapy. Citation Format: Olivier Raguin, Marie Leblanc, Bertrand Collin, Alexandra Oudot, Jean-François Mirjolet, Ulrike Fiedler, Ignacio Dolado. Biodistribution and antitumor efficacy study of novel Her2 targeting DARPins. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5442. doi:10.1158/1538-7445.AM2014-5442

Small molecule tyrosine kinase inhibitors of ErbB2/HER2/Neu in the treatment of aggressive breast cancer.

The human epidermal growth factor receptor 2 (HER2) is a member of the erbB class of tyrosine kinase receptors. These proteins are normally expressed at the surface of healthy cells and play critical roles in the signal transduction cascade in a myriad of biochemical pathways responsible for cell growth and differentiation. However, it is widely known that amplification and subsequent overexpression of the HER2 encoding oncogene results in unregulated cell proliferation in an aggressive form of breast cancer known as HER2-positive breast cancer. Existing therapies such as trastuzumab (Herceptin®) and lapatinib (Tyverb/Tykerb®), a monoclonal antibody inhibitor and a dual EGFR/HER2 kinase inhibitor, respectively, are currently used in the treatment of HER2-positive cancers, although issues with high recurrence and acquired resistance still remain. Small molecule tyrosine kinase inhibitors provide attractive therapeutic targets, as they are able to block cell signaling associated with many of the proposed mechanisms for HER2 resistance. In this regard we aim to present a review on the available HER2 tyrosine kinase inhibitors, as well as those currently in development. The use of tyrosine kinase inhibitors as sequential or combinatorial therapeutic strategies with other HER family inhibitors is also discussed.

Clinical value of trastuzumab in the treatment of lapatinib-resistant HER2-positive metastatic breast cancer

Retrospective and prospective studies have shown that continuous administration of trastuzumab with different chemotherapy regimens resulted in better clinical outcomes than the administration of chemotherapy alone in women with HER2-positive, trastuzumab-refractory metastatic breast cancer (MBC). However, there are limited data to evaluate the activity of trastuzumab in patients progressed after other anti-HER2 therapies, e.g. lapatinib. The aim of the present study was to evaluate retrospectively the clinical value of trastuzumab in patients with lapatinib-resistant HER2-positive advanced breast cancer treated in our center. Patients with HER2-positive MBC who experienced progression after first-line lapatinib-based regimens were assigned to receive either conventional treatment without trastuzumab or in combination with trastuzumab as second-line therapy. The efficacy end points included progression-free survival (PFS) and overall survival (OS). Thirty-five eligible patients progressed after treatment with lapatinib-based regimens were collected. None of the patients had received prior trastuzumab in either the adjuvant or metastatic setting. Twenty-two patients were assigned to receive conventional treatment without trastuzumab as second-line therapy (non-T arm) and 13 patients received conventional treatment combined with trastuzumab (T arm). There were no significant differences in the main clinical factors between the two arms, such as age, PS status, ER/PR, metastatic status, etc. Both the two cases with no disease progression after the second-line therapy were trastuzumab-treated patients, and all the other 33 cases were patients with progression despite the second-line therapy. Twenty-seven patients died due to disease progression, and eight survived (six cases of the T-arm and two cases of the non-T arm). The median PFS was 3.3 months in the non-T arm and 10.0 months in the T arm (P = 0.001). The median OS was 7.0 months in the non-T arm and 31.1 months in the T arm (P = 0.015). Trastuzumab plus conventional treatment is superior to conventional treatment in women with lapatinib-resistant HER2-positive metastatic breast cancer. Continuous anti-HER2 management can provide survival benefit to patients with HER2-positive breast cancer.

EXPRESSION AND PURIFICATION OF A SOLUBLE ESX-BINDING CORE DOMAIN OF SUR2

For HER2 overexpression, the ESX transcription factor must interact with both the HER2 promoter and Sur2, a subunit of human mediator complex, using its Ets domain and transactivation domain, respectively. HER2 overexpression is a marker of poor prognosis in various types of cancers. Thus, interfering with the ESX-Sur2 interaction has been suggested as a novel strategy for the treatment of HER2 positive cancers. To design small molecule inhibitors against the ESX-Sur2 interaction, it is necessary to identify the structure of the interface of ESX-Sur2 binding. Therefore, in this study, we determined the optimal conditions for the overexpression and purification of a new version of Sur2, Sur2391-582, which was able to bind to ESX. To stabilize (His)6-Sur2391-582, various different buffered conditions over a wide range of pH and ionic strengths were examined. The molecular mass of (His)6-Sur2391-582 was determined using mass spectroscopy and size exclusion chromatography. The purified (His)6-Sur2391-582 protein displayed the same biological properties as that of the Sur2 full-length protein.

Clinical progress in treatment of HER2 positive breast cancer with trastuzumab

Clinical studies have shown that trastuzumab combined with chemotherapy can significantly improve survival in treatment of HER2-positive metastatic breast cancer as well as in the neoadjuvant and adjuvant therapy for HER2-positive early breast cancer. In patients with HER2-positive and hormone receptor-positive metastatic breast cancer, adding trastuzumab to endocrine therapy improves treatment efficacy. Resistance to trastuzumab may be reversed by incorporating other targeted therapeutic drugs. Patients can still benefit from continuing trastuzumab after their disease progresses. Key words: Breast neoplasms; Receptor,epidermal growth factor

Abstract 2581: Development of an Fc-domain-optimized monoclonal antibody with enhanced potency against HER2-expressing tumors

Abstract Polymorphic variants of the activating Fcγ receptors (FcγR) expressed in metastatic breast cancer patients predict response duration to trastuzumab [Musolino J Clin Oncol 26:1789 2008]. Patients homozygous for the 158V variant of FcγRIIIA (CD16A) have longer progression-free survival than those carrying the 158F variant. CD16A-158V binds the Fc domain of IgG1 with higher affinity than CD16A-158F. Because <20% of all individuals are CD16A-158V homozygous, only a minority of the patient population will fully benefit from trastuzumab treatment. Furthermore, the benefit of trastuzumab only accrues to patients whose tumor is “addicted” to HER2 overexpression, with no perceived benefit to those expressing HER2 at the ≤2+ level without gene amplification. MGAH22 is a human/mouse chimeric IgG1 anti-HER2 monoclonal antibody (mAb) that has been engineered to increase the affinity of the Fc domain for both CD16A alleles and decrease the affinity for the inhibitory receptor, FcγRIIB (CD32B). MGAH22 maintains the anti-proliferative activity of the parental mAb (4D5, the precursor to trastuzumab) and exhibits improved antibody-dependent cell cytotoxicity (ADCC) compared to an identical mAb with a wild type Fc domain. The greatest improvement in ADCC activity was observed on low HER2-expressing target cells and with effector cells isolated from donors homozygous or heterozygous for CD16A-158F, the low-binding CD16A allele. MGAH22 also exhibited enhanced antitumor activity against a trastuzumab-resistant HER2+ tumor (JIMT-1) in xenograft experiments conducted in mice transgenic for human CD16A-158F. In a repeat-dose toxicology study in cynomolgus monkeys, there were no test article-related findings except for non-adverse dose-independent reductions in circulating natural killer (NK) cells that were not accompanied by decreased NK cell cytolytic activity. A transient induction of serum IL-6 levels occurred within 4 hours of infusion with MGAH22 or, to a lesser extent, vehicle. The terminal half-life of MGAH22 in cynomolgus monkeys was approximately 7 to 9 days and the NOAEL was determined to be 150 mg/kg. These data support the clinical development of MGAH22 as a treatment of HER2-positive cancers, particularly in CD16A-158F carriers. Patients that may benefit from treatment with MGAH22 include: (i.) breast cancer patients whose tumors overexpress HER2 at the 2+ level and do not exhibit gene amplification, (ii.) breast cancer patients whose tumors overexpress HER2 and have progressed on trastuzumab therapy and (iii.) patients with certain other solid tumors that overexpress the HER2 oncoprotein at the 2+ or 3+ level and for whom trastuzumab therapy has not been demonstrated to be beneficial. A Phase 1 dose escalation study to assess MGAH22 in patients with HER2-positive tumors is expected to initiate in 2010. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2581.