Oncology Highlights - May 2018
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Enjoy reading! - The SMS-oncology team
In Darwinian terms, adaptation to a new regime comes with the fitness cost. Gained drug resistance of cancer cells results in a fitness cost that in return can cause sensitivity in other pathways referred to as ‘‘collateral sensitivity’’. Researchers from the Netherlands Cancer Institute (NKI) identified the proverbial ‘Achilles heel’ in BRAF mutated / BRAF inhibitor (BRAFi) resistant melanoma using this collateral sensitivity. More than half of all melanoma patients have a mutation in this BRAF gene. For these people, the targeted therapy with BRAF-inhibitor stops tumor growth. However, within a few months the tumor cell adapts the original signaling pathway becomes active again gaining resistance to BRAF-inhibitor therapy. Scientists from the NKI characterized the BRAFi resistant cell lines for their differential expression and identified 2-fold increased basal levels of reactive oxygen species (ROS) production because of activated RAS signaling. Hypothesizing that this increase in ROS levels may represent an acquired vulnerability and that when ROS levels are further induced it will be lethal in these drug-resistant cells, they tested ROS inducer vorinostat – a HDACi that has been in the clinic for 15 years- in mouse xenograft models. Results backing their theory, vorinostat treatment, inducing ROS levels even further, inhibited only the proliferation resistant melanoma cells, shrinking the tumor. Previously combination therapy with BRAF and HDAC inhibitors was shown to prevent the emergence of resistant melanoma cells, which is different from the sequential use of these drugs in this study. The researchers from the NKI emphasize the advantages of sequential use as it decreases the toxicity, enabling the clinical use of a much larger drug repertoire in comparison to simultaneous use. The study was published in Cell.
Researchers from the University of Southern California (USC) have identified a method to inhibit a protein that is involved in breast cancer metastasis. TNBC makes up 20% of breast cancer cases and it is highly metastatic with limited therapeutic options. Previous studies showed the TAK1 protein is responsible for lung metastasis in TNBC patients, and inhibition of TAK1 with an already existing drug called 5Z-7-Oxozeaenol - or OXO - can in theory impede breast cancer cells to form lung metastases. However, OXO is not stable in the blood, and therefore could not be used in patients. The USC team collaborated with the USC Viterbi School of Engineering to overcome the short half-life of OXO. Developing a nanoparticle to load the OXO, a cross-linked multilamellar liposomal vesicle (cMLV), they engineered a smart bomb to carry drugs through the bloodstream and deliver them directly to tumors. This nanoparticle loaded with OXO was used it to treat mice that had been injected with human breast cancer cells. While OXO did not shrink primary tumors in the breast, it greatly reduced metastatic tumors in the lungs with minimal toxic side effects. The preclinical study shows promise and more research will be conducted before it reaches to clinical trials. The findings were published in Nature communications.
Eli Lilly strengthens its immuno-oncology (IO) portfolio with two new acquisitions. On May 10th, the company announced the $1.6 billion deal with ARMO biosciences, gaining access to its IO platform and phase III stage lead product candidate pegilodecakin, a PEGylated interleukin-10. It is the fastest post-IPO exits seen for a while coming just four months after ARMO went public. Pegilodecakin demonstrated clinical benefit as a single agent and in combination studies with both chemotherapy and checkpoint inhibitors across several tumor types including pancreatic cancer, lung, renal cell cancer, melanoma and other solid tumor types. The second deal in May was announced just four days after the buy of ARMO, this time AurKa Pharma with its early stage drug candidate. In this $576 million deal, Lilly gets hold of the Aurora kinase A inhibitor dubbed AK-01 which showed promising results in phase I studies.
The oncolytic virus therapy field is heating up as major cancer players search for drugs to complement checkpoint inhibitors and other IO therapies. The recent example is the upfront payment of Jonhson&Johnson to BeneVir and commitment to its T-Stealth technology with a total of more than $1 billion for milestones. Although in preclinical stage, BeneVir its platform is designed similar to the other oncolytic viruses: they replicate and kill their host, triggering an immunogenic tumor cell death. The difference is that T-Stealth technology shields its viruses to avoid being eliminated by T cells. Although, BeneVir has yet to validate this hypothesis in clinics, J&J has been evidently convinced enough with the preclinical results.
Xenikos, a Dutch clinical stage IO biotech secures $30 million in series B funding, enabling them to start the pivotal trial in the US. The planned registry phase III trials in both EU and US may lead to getting MAA from the FDA/EMA for their lead candidate T-Guard aiming to help patients with Graft versus Host Disease (GvHD). Often leukemia patients get GvHD after a stem cell transplantation, in which the donor cells are attacking the patient its body. With the encouraging phase I/II study results, Medicxi Ventures and RA Capital Management are confident that Xenikos its T‑Guard has the potential to help cure patients with GvHD. Xenikos’ T-Guard (2 antibodies coupled to an immunotoxin) aims to kill the T and NK cells that are causing GvHD. Meanwhile, the neighboring Belgian biotech Celyad raises $47 million funding on Euronext Paris and the NASDAQ to give a boost its CAR-T cell therapy. Its most advanced candidate CYAD-01 is currently in Phase I studies targeting both solid tumors and hematological malignancies.
The Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion for:
The FDA granted regular approval for:
- Dabrafenib and trametinib (TAFINLAR and MEKINIST, Novartis) in combination for the adjuvant treatment of patients with melanoma with BRAF V600E or V600K mutations. The kinase inhibitor combination is also approved for the first-line treatment of patients with metastatic NSCLC (with EGFR exon 19 deletions or exon 21 L858R mutation).
- Tisagenlecleucel (KYMRIAH, Novartis) for adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy including diffuse large B-cell lymphoma (DLBCL). This CD19 targeting autologous T-cell immunotherapy is also approved - if not otherwise specified - for high-grade B-cell lymphoma and DLBCL arising from follicular lymphoma.
- Dabrafenib and trametinib (TAFINLAR and MEKINIST, Novartis) in combination for the treatment of patients with locally advanced or metastatic anaplastic thyroid cancer (ATC) with BRAF V600E mutation and with no satisfactory locoregional treatment options.