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Chemotherapy is getting ‘smarter’ “The field of truly bifunctional fusion molecules ... working against resistant disease, may prove to be a strong and tolerable combination partner for targeted therapies, much to the benefit of patients.” Thomas Mehrling* Chemotherapy is becoming ‘smarter’, specifically targeting and killing tumor cells without affecting healthy cells. This revolution in cancer treatment provides the potential to improve treatment efficacy and tolerability, ultimately improving patient outcomes. Past attempts to improve treatment efficacy, by inventing various combinations of cytotoxic agents, have provided disappointing results. Patients, mostly treated in large cooperative trials, experienced little benefit from intensification of dose and schedule but instead suffered from frequent and severe adverse reactions. Such an example was the futile attempt to treat metastatic breast cancer with ablative high-dose chemotherapy and subsequent stem cell transplantation, which resulted in significant mortality [1] . Consequently, a number of established chemotherapy regimens such as CHOP (cyclophosphamide, hydroxydaunomycin [doxorubicin], vincristine [Oncovin®, Cellpharm GmbH, Hannover, Germany], prednisolone) for lymphoma, melphalan-prednisone for multiple myeloma or platinum-based therapy for lung cancer were the standard of care for decades, and during this period patient mortality was high [2] .

In recent years, we have seen the introduction of targeted therapies such as imatinib for chronic myeloid leukemia and gastrointestinal stromal tumor, or erlotinib for lung cancer with mutation of the EGFR. Other targeted therapies include antibodies that recognize cell surface markers (e.g., CD20) which trigger an immune response or stop signal cascades, as is the case with bevacizumab which inhibits VEGF [3] . The combination of new targeted therapies and existing chemo­therapy has resulted in considerable improvement in outcomes. Some cases have even led people to believe that classical chemotherapy could become redundant, these include those where a single mutation is driving the proliferation of the malignant clone in chronic myeloid leukemia, or where there is the strong dependence of chronic lymphocytic leukemia, or in lymphomas resulting from B-cell receptor signaling. A similar trend occurred in the field of HER2-positive breast cancer, where a tumor of the worst prognosis turned into one of the most treatable cancers following the introduction of new medicines, such as trastuzumab and lapatinib, which stop HER2 signaling [4,5] . These innovations triggered the development of similar drugs,

KEYWORDS 

• antibody–drug conjugate • chemotherapy • fusion molecule • histone-deacetylase inhibitor

“Chemotherapy is becoming ‘smarter’, specifically targeting and killing tumor cells without affecting healthy cells.”

part of

*Mundipharma EDO GmbH, Basel, Switzerland; [email protected]

10.2217/FON.14.248 © 2015 Future Medicine Ltd

Future Oncol. (2015) 11(4), 549–552

ISSN 1479-6694

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Editorial Mehrling

“Past attempts to improve treatment efficacy, by inventing various combinations of cytotoxic agents, have provided disappointing results.”

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often with an improved risk/benefit profile, giving patients a wider choice of treatment options than ever before. Classical chemotherapy now finds itself at crossroads. In some cancers, treatment is increasingly reliant on just targeted therapies, whereas in others the demand for a less toxic combination of chemotherapy and targeted therapies creates the need for different drugs or ‘smarter’ ways to deliver chemotherapy to the tumor. Furthermore, tolerability issues in older patients have led to provision of insufficient therapy and unsatisfactory outcomes. This situation continues and is unacceptable given society’s growing elderly population. As demand drives innovation chemotherapy is about to evolve, more effectively targeting tumor cells while reducing damage to healthy tissues. Two important trends are emerging: the development of antibody–drug conjugates (ADCs) and the exploitation of synergies of targeted and cytotoxic therapy through fusion molecules. Antibody–drug conjugates The concept of ADCs seems as obvious as it is intriguing. A selective tumor-specific antibody is linked to a highly potent cytotoxic drug, which is delivered to the interior of cancer cells while largely sparing normal cells that lack expression of the target antigen. Initial attempts to develop ADCs were hindered by the inability to produce stable antibody–drug combinations [6] . The first compound, levofloxacin, targeted CD33 proteins on acute myeloid leukemia cells, but suffered from an unstable antibody–drug linker, which led to cleavage in systemic circulation before reaching the target cell and significant systemic toxicity. Levofloxacin was subsequently withdrawn from the market, before later studies showed the benefits of using the drug in consolidation therapy [7–9] . It took years of work on advancing linking technologies to create ADCs that were stable in the blood stream and only release the cytotoxic agent once inside the tumor cell. The approvals of brentuximab vedotin (BV), which targets CD30 proteins, for the treatment of rare lymphomas (Hodgkin’s lymphoma and peripheral T-cell lymphoma) and trastuzumab emtansine, for the treatment of HER2-positive metastatic breast cancer patients, were s­ignificant milestones in the ADC field [10,11] . Potent chemotherapies, such auristatin and maytansinoid agents, could not be given systemically as the toxicity is far too high; however,

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coupling such agents with a tumor-specific antibody has resulted in significant treatment response and improved outcomes for patients. In patients with relapsed/refractory Hodgkin’s lymphoma, the overall response rate to BV was 85% with tumor reduction in 97% of patients [12] . These ground-breaking results were recognized by regulators and accelerated approvals were granted in both the USA and Europe [13] . Likewise, a Phase I study in which BV was administered as front-line treatment, either with the combination of doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) or AVD (ABVD without bleomycin), showed that BV and AVD can be given safely and provided an impressive complete remission rate of 96% [14] . Based on these remarkable results, BV is now being evaluated in a Phase III trial including treatment-naive patients with Hodgkin’s lymphoma. If positive, the results of this study will redefine the practice of front-line therapy and highlight the potential for BV to change the prognosis of young patients with Hodgkin’s lymphoma. Less complex curative chemotherapy may also reduce the long-term toxicity associated with current treatment, notably lung toxicity related to bleomycin and the cardiovascular toxicity of anthracyclines, which can last for 35 years [15] . These successes with ADCs clearly show chemotherapy is evolving and, with the invention of stable linkers, it may be possible to utilize cytotoxic agents against a greater selection of targets. There are many new compounds in development using new highly potent drugs with different modes of action to improve and ­optimize cancer treatment. Fusion molecules: histone deacetylase inhibition The second evolution in chemotherapy, albeit behind ADCs in clinical development, is equally interesting. Fusion molecules either combine an established chemotherapy principle with a synergistic targeted mode of action in one molecule or through a combination of chemotherapeutic drugs with targeted compounds. By exerting their dual action simultaneously, fusion molecules may overcome the difficulties of combining single agents with different pharmacokinetics and other pharmacological factors. Moreover, this concept may allow the exploitation of combining drugs with synergistic modes of action, leading to improved efficacy. One fusion molecule, currently in development, combines the strong

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Chemotherapy is getting ‘smarter’  alkylating activity of bendamustine with the h­istone deacetylase (HDAC) inhibitor vorinostat. Tumors control gene expression and protein synthesis through epigenetic modifications of histones. Consequently, certain tumor suppressor genes, and/or genes controlling apoptosis, are silenced mainly by increased HDAC activity and/or decreased activity of histone acetyltransferases. Several HDAC inhibitors exist, either acting as pan-HDAC inhibitors or as single isoform compounds for the different class 1 and 2 enzymes. Inhibition of HDAC function and modification of gene expression has resulted in substantial activity in vitro, but clinical investigation demonstrated comparatively modest activity [16] . Research now focuses on the particular function of isoforms, with recent findings supporting a role of HDAC 6 and 8 in resistance to therapy in multiple myeloma and HDAC 10 in brain tumors such as neuroblastoma. Various hypotheses suggested HDAC inhibition may lead to synergy with DNA-damaging agents by abrogating DNA double-strand break repair. This was supported by the discovery of the higher expression of p-H2A, a marker of activated DNA repair, and the activation of checkpoint protein Chk2. The combination of DNA-damaging agents, or ionizing radiation with HDAC inhibitors, showed synergism or at least additive effects in many cancer cell lines. The molecular mechanisms showing how HDAC inhibition enhances the efficacy of antitumor agents and radiotherapy are not yet fully understood; however, studies have found that HDAC inhibition relaxes chromatin through increased acetylation of histones, which makes the chromatin more easily accessible to DNA-damaging agents [17] . References 1

National Cancer Institute. High-dose chemotherapy for breast cancer: history. www.cancer.gov

2

Dotan E, Aggarwal C, Smith MR. Impact of rituximab (Rituxan) on the treatment of B-cell non-Hodgkin’s lymphoma. P. T 35(3), 148–157 (2010).

3

EMA. Summary of product characteristics. Avastin. Roche. www.ema.europa.eu

4

EMA. Summary of product characteristics. Herceptin. Roche. www.ema.europa.eu

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The synergies of HDAC inhibition and DNAdamaging agents, such as alkylators, provided the rationale for the synthesis of the first-in-class fusion molecule bendamustine–vorinostat. The assumption was that the molecule that would not be cleaved in circulation, but having full capability to exert its bifunctional activity in cancer cells would be the optimal approach to exploit the synergies of both modes of action. It is anticipated that this fusion molecule may have strong activity in various hematological malignancies and solid tumors. The initial focus of preclinical development is on investigating its mode of action in multiple myeloma, aggressive B- and T-cell lymphomas and Hodgkin’s lymphoma; and among solid tumors, glioblastoma and other CNS cancers, soft tissue sarcoma, gastrointestinal stromal tumor and metastatic or triple-negative breast cancer. The field of truly bifunctional fusion molecules is still in its infancy but may help chemotherapy get ‘smarter’ [18] . These compounds, working against resistant disease, may prove to be a strong and tolerable combination partner for targeted therapies, much to the benefit of patients.

Editorial

“As demand drives

innovation ... [t]wo important trends are emerging: the development of antibody–drug conjugates and the exploitation of synergies of targeted and cytotoxic therapy through fusion molecules.

Financial & competing interests disclosure T Mehrling is the Managing Director of Mundipharma EDO GmbH, Basel, Switzerland, the company that develops the alkylating HDAi fusion molecule. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Editorial assistance was provided by Makara Health Communications Limited and was funded by Mundipharma EDO GmbH.

5

EMA. Summary of product characteristics. Tyverb. GSK. www.ema.europa.eu

6

Fitzgerald DJ, Wayne AS, Kreitman RJ, Pastan I. Treatment of hematologic malignancies with immunotoxins and antibody–drug conjugates. Cancer Res. 71(20), 6300–6309 (2011).

7

Burnett AK, Hills RK, Hunter AE et al. The addition of gemtuzumab ozogamicin to intensive chemotherapy in older patients with AML produces a significant improvement in overall survival: results of the UK NCRI AML16 randomized trial. ASH Annual Meeting Abstracts 118(21), 582 (2011).

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Castaigne S, Pautas C, Terre C et al. Fractionated doses of gemtuzumab ozogamicin (GO) combined to standard chemotherapy (CT) improve event-free and overall survival in newly-diagnosed de novo AML patients aged 50–70 years old: a prospective randomized Phase 3 trial from the Acute Leukemia French Association (ALFA). Blood 118(21), 6 (2011).

9

FDA. Mylotarg (gemtuzumab ozogamicin): market withdrawal. www.fda.gov

10 EMA. Summary of product characteristics.

Acetris. Takeda. www.ema.europa.eu

www.futuremedicine.com

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Editorial Mehrling 11 EMA. Summary of product characteristics.

Kadcyla. Roche. www.ema.europa.eu 12 Garnock-Jones KP. Brentuximab vedotin:

a review of its use in patients with hodgkin lymphoma and systemic anaplastic large cell lymphoma following previous treatment failure. Drugs 73(4), 371–381 (2013). 13 EMA. Summary of product characteristics.

Adcetris. Takeda Pharma A/S. www.ema.europa.eu

15 Van Nimwegen FA, Schaapveld M,

Janus CPM et al. Cardiovascular diseases after Hodgkin lymphoma treatment: 35-year disease risk and sequence of events. J. Clin. Oncol. 32(Suppl. 15), 9505 (2014). 16 Thurn KT, Thomas S, Moore A, Munster

14 Younes A, Connors JM, Park SI et al.

Brentuximab vedotin combined with ABVD

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or AVD for patients with newly diagnosed Hodgkin’s lymphoma: a Phase 1, open-label, dose-escalation study. Lancet Oncol. 14(13), 1348–1356 (2013).

PN. Rational therapeutic combinations with histone deacetylase inhibitors for the

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treatment of cancer. Future Oncol. 7(2), 263–283 (2011). 17 Groselj B, Sharma NL, Hamdy FC, Kerr M,

Kiltie AE. Histone deacetylase inhibitors as radiosensitisers: effects on DNA damage signalling and repair. Br. J. Cancer 108(4), 748–754 (2013). 18 López-Iglesias A. Preclinical anti-myloma

activity of the alkylating-HDACi molecule EDO-S101 through DNA-damaging and HDACi effects. Haematologica 99(Suppl. 1), 1–796; P942 (2014).

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Chemotherapy is getting 'smarter'.

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