Brazil enters advanced cancer drug research.

Aché Pharmaceutical: Brazil is taking early steps that should cause it to rise up the world’s cancer research rankings, thanks to a joint initiative between its leading commercial pharmaceutical company and a highly innovative drug discovery consortium.

The very first fruits of Brazil’s new collaboration are now visible. Newly-published research into human kinase proteins associated with tumour formation, could one day position it as a producer of tyrosine kinase inhibitor (TKI) drugs of the type now at the forefront of the battle against lung cancer.

At present, such drugs manufactured by multinationals are so expensive as to be completely beyond the reach of Brazilians with lung cancer.

Tarceva (Erlotinib), a first-generation TKI made by Roche, costs up to US$8,600 a month in the US outside Medicaire. Meanwhile Tagrisso (Osimertinib), a third generation TKI manufactured by AstraZeneca, costs around US$14,500 per month. Even in developed countries, these life-saving drugs may be distributed only if manufacturers agree to steeply-discounted government programmes.

Such TKIs carry “cease and desist” orders to multiplying tumour cells and so prevent their growth – until such time as the cells mutate to new and resistant types. Understanding the cell reproduction instructions that lead to uncontrolled growth, and unravelling the evolutionary process driving mutations within tumours, is the hot zone for cancer research globally.

Kinase chemical biology holds key to advanced drug discovery

Kinase chemical biology holds key to advanced drug discovery

A pioneering study by the Brazilian-led group into Vaccinia-related protein kinases (VRK), VRK1 and VRK2 published last August by Nature’s Scientific Reports, could be the starting point for the development of chemical probes implicated in cell cycle control. These in turn could eventually be engineered into potent and specific inhibitors of runaway cell clusters that characterise cancerous tumours.

The study brings together researchers from the Centre for Molecular Biology and Genetic Engineering at the University of Campinas; from Aché Pharmaceutical Laboratories; and from the Structural Genomics Consortium (a Toronto-based not for profit body dedicated to IP-free early stage drug discovery).

The Scientific Reports lead author is Rafael Couñago, a Campinas university researcher. But Opher Gileadi of the SGC and Target Discovery Institute, and Oxford University’s Nuffield Department of Clinical Medicine, who was responsible for the January 2016 establishment of the SGC labs at Campinas, is one of the report’s co-authors. Aché is represented by  researcher Fernando H. de Souza Gama.

Almost all kinase structures continue largely unresearched

Almost all kinase structures continue largely unresearched

Lead author Couñago told a Brazilian journalist: “once we can obtain chemical probes with the desired characteristics, researchers can then use this tool to test  how to prevent VRK involvement in some types of cancer. This is the way we can confirm whether inhibiting the action of these proteins will affect tumour cells, and, in turn, validate the use of these enzymes for therapeutic purposes.”

While it’s a very long mile between publishing research papers and actually discovering marketable drugs, in other geographies SGC and its partners have proven  that they can dramatically reduce the time needed to bring drugs to Phase II trial status, thanks to a collaborative “Pharmaceutical Commons” or IP-free approach.

Using SGC's open model drug  discovery reaches  Stage II trials faster and cheaper.  Image by Martin School/SGC

Using SGC’s open model drug discovery reaches Stage II trials faster and cheaper. Image by Martin School/SGC

A recent study by Oxford University’s Martin School highlighted the SGC’s open data approach as being responsible in one case for a new cancer drug co-developed with GSK reaching first-stage trials in just 16 months. The new approach comes as data from the FDA shows that the number of new drugs approved per billion US dollars spent on research falls by 50% every nine years for multinationals adopting the closed or IP-driven model demanded by investors and stock markets.

New SGC labs at Campinas

The SGC labs at Campinas

The Scientific Reports paper represents one of the first fruits of a strategy to create a biotech and high-tech pharma cluster around Campinas, described in detail an earlier SFB article.

The strategy relies upon an open model to fast-track any fruitful research toward the later stages of drug discovery – and contrasts with far costlier and much slower closed model still favoured by publicly-listed pharmaceutical multinationals.

Although Brazil is the world’s eight largest drugs market with estimated annual sales of US$41 billion in 2017, it is almost wholly dependent on multinational companies for cancer drugs, despite having an estimated 224,000 cancer-related deaths per year, according to Cancer Index. In 2014, 37,330 cases of lung cancer were recorded.

Nevertheless Brazil has been a back marker in cancer research and is cited in one paper (Elsevier’s Journal of Thoracic Oncology) as having one of the world’s lowest levels of research output on lung cancer amongst 24 nations producing research, with just 184 papers published during the 2004-2013 period. This compares with the US and China which in 2013 alone published 1374 papers and 1283 papers respectively. This puts Brazil alongside Norway and Austria at the very bottom of the cancer-related publishing rankings (see chart).

Brazil  joins  Austria as backmarker in  published  research on  lung cancer. Elsevier data with  Creative Commons licence.

Brazil joins Austria as backmarker in published research on lung cancer. Elsevier data with Creative Commons licence.

But now everything could change, even though it will be years before the Campinas research, combined with initiatives by Aché Pharmaceutical, yields fruit. Brazilian-owned Aché is a 50 year-old company which is also an investor in Bionovis S.A., a Brazilian biopharmaceutical company. This business plans to invest R$500 million over the next 5 years in biotech research into proteins similar to VRK1 and VRK2.

The Campinas-based partnership between Aché and SGC will support the Brazilian company’s self-proclaimed “goal to become the innovation leader among national pharmaceutical companies and to achieve a global reach.”

Aché’s so-called ‘Radical Innovation’ department, under the leadership of Cristiano Guimarães, was responsible for the molecular modelling and structural design component of the research project. Guimarães told a Brazilian journalist: “we designed and created 97 test molecules for use in in vitro assays with the VRK1 Kinase.” Another article will be published in early 2018, describing this process.

This kind of leading-edge research into cancer could help Brazil’s own drug industry turn the corner from dependence on generics or older drugs with expired patents described in this SFB article, toward new generation therapies of the type now being researched and marketed by Astra Zeneca, Novartis and Roche.

"G is for Generics"

“G is for Generics”

The Campinas research and the SGC laboratory there are receiving financial support from FAPESP, the São Paulo Research Foundation, the lead agency for supporting scientific innovation in Brazil’s economic powerhouse.

Even though cancer research might at first blush sound like an unaffordable luxury for a developing country and be likely to expensively duplicate more advanced scientific inquiry carried out elsewhere,  in  decades to come the strategic thinkers behind Brazil’s dawning era of drug innovation may turn out to have played a true winning hand.

You can read a detailed article (in Portuguese) by Brazilian journalist Karina Toledo by clicking here.

The (open access) article in Scientific Reports can be seen here: www.nature.com/articles/s41598-017-07755-y.

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