Inhibiting Myc and the Myc dependent inflammatory response as cancer therapies.

Daniel Massó Vallés

Dra. Laura Soucek

This doctoral thesis describes two products with undoubted industrial and commercial interest: ibrutinib for the treatment of pancreatic cancer and Omomyc for the treatment of breast cancer. In addition, both drugs have the potential to be applicable against other pathologies. Ibrutinib The first product is the drug ibrutinib (trade name Imbruvica) and is already established on the market for the treatment of some diseases. Ibrutinib is an inhibitor of a molecule called BTK, essential for the functioning of a type of immune system cell known as B lymphocytes1. B lymphocytes are the cause of some types of hematological cancers, and that is why ibrutinib is so effective in their treatment. It is used to treat certain leukemias and lymphomas, and in three of these pathologies it already constitutes the first line of treatment: chronic lymphocytic leukemia2, mantle cell lymphoma3 and Waldenström macroglobulinemia4. Ibrutinib is the main product of Pharmacyclics LLC (www.pharmacyclics.com), a pharmaceutical company located in Sunnyvale, California (USA) with which we have collaborated closely. Pharmacyclics was acquired in 2015 by the pharmaceutical company AbbVie (Chicago, USA) for 21 million dollars, with estimated sales of ibrutinib worth 1 billion dollars in 2016 and 5 billion in 2020. - A new property of ibrutinib could extend its use to pancreatic cancer The results of this thesis are based on a previously unknown property of ibrutinib that could allow its market to be expanded to the treatment of solid tumors, a type of cancer completely different from leukemia or lymphoma. Mast cells are a type of cell that play an important role in pancreatic cancer and whose function also depends on BTK. As described in the thesis, we used ibrutinib in mouse models of pancreatic cancer and found that we were able to reduce tumor growth. In addition, we observed that the treatment had an unexpected effect on the tumor stroma. The stroma is a fibrotic layer, composed mainly of collagen fibers, that surrounds the tumor and acts as a protective barrier, preventing conventional drugs from efficiently reaching the tumor. Through the inhibition of mast cells, treatment with ibrutinib reduced this fibrotic layer and allowed chemotherapy to penetrate to the center of the tumor, increasing the survival of the mice and demonstrating that the addition of ibrutinib to conventional therapy could become an effective strategy for patients with pancreatic cancer5. Along these lines, the anti-fibrotic property described in this thesis led to the registration of a patent by Pharmacyclics, of which I am the inventor (international patent number PCT/US2015/063475, 2016)6. Omomyc With an original and innovative mechanism of action, Omomyc is able to overcome these obstacles. It can block the function of the 3 proteins of the Myc family11-13 and presents key advantages over conventional therapies: it has demonstrated extraordinary efficacy regardless of the mutations that the tumor has, the side effects it causes are mild and reversible and so far the emergence of resistance has not been detected in any of the models studied14,15. Omomyc has been extensively used as a transgene in preclinical models, that is, it has been introduced through genetic engineering into human cells in culture and transgenic mice. This has served to demonstrate that the inhibition of Myc is highly effective against multiple types of cancer14-18, including metastatic breast cancer as discussed in this doctoral thesis. However, until now these studies have only constituted a “proof of concept” since they could not be transferred to humans. Recently, Dr. Soucek and Dr. Beaulieu created the spin-off Peptomyc S.L. (www.peptomyc.com), with the aim of converting Omomyc into a drug to be administered to patients. Peptomyc is located at VHIO and we collaborate closely with it.

Ibrutinib Our results, together with those of another group7, led to the design and initiation of coordinated clinical trials between different countries in Europe, America and Asia to compare the survival of pancreatic cancer patients treated with conventional chemotherapy with that of patients treated with chemotherapy and ibrutinib (phase 1/2 clinical trial: NCT025628988 and phase 2/3 clinical trial: NCT024366689). These trials are currently underway and the first results will be known in the next 2 or 3 years. If these results are satisfactory, the quality and life expectancy of these patients could improve substantially. Given the poor prognosis of this disease, combined with the fact that ibrutinib has already passed all the toxicity tests required for its marketing, confirmation that this drug is effective against pancreatic cancer would mean immediate approval by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA). Omomyc Breast cancer is the most common cancer and the leading cause of cancer mortality in women, mainly due to the high incidence of metastasis, which, to this day, remains incurable. Every year, more than 1.7 million women are diagnosed with breast cancer20 (2012 data), and according to the World Health Organization, 500,000 die as a result of the disease21. Between 15 and 20% of breast cancers belong to the “triple negative” subtype, a group of more aggressive cancers that do not have targeted therapies, so surgery, chemotherapy and radiotherapy remain the only treatments. The breast cancer market has remained stable in recent years (around 10 billion dollars). For a therapy to open up a space in this market, it must constitute a significant advance and provide a substantial improvement to justify its use. Metastatic breast cancer has a poor prognosis and, despite the emergence of new therapies, the best strategy for treating it has not yet been established and mortality remains high (in some subtypes it reaches 80%). TMTP1-Omomyc could have a very positive impact on the treatment of the disease, and would probably enter as a second line in “triple negative” breast cancer. However, the impact of Omomyc and its variants such as TMTP1-Omomyc is not limited to breast cancer, since its use could potentially extend to any type of cancer. In fact, Omomyc has shown extraordinary effects in models of non-small cell lung cancer, pancreatic ductal adenocarcinoma and glioblastoma14,15,18 and unpublished data, diseases with urgent needs for new therapies. Metastasis is the leading cause of cancer death, and in this thesis we demonstrate for the first time that Omomyc has anti-metastatic properties, suggesting that it could be used against the most aggressive cancers. The fact that some of these cancers are considered “orphan” due to lack of therapies means that there are incentives when entering clinical trials, incentives that translate into lower costs or acceleration of review processes for approval. 75% of the oncology market is concentrated in the United States, the 5 largest European countries and Japan. However, the increase in cancer prevalence and improved access to treatments in many countries will cause spending on anti-cancer drugs to grow from 100 billion dollars in 2014 to 117 billion dollars in 2018 according to the IMS Institute. An effective Myc inhibitor would have the potential to capture a substantial portion of this market, considering that it could be used in the treatment of multiple types of cancer. Another IMS report concludes that the market for biological therapies such as Omomyc is expanding, with an increase of 70% in the last 5 years, reaching 232 billion dollars22. Since its creation, Peptomyc has managed to raise 2 million euros in public grants. In April 2016, a first investment round of 1 million euros was closed with venture capital (HealthEquity) and Business Angels. In 2017, Peptomyc closed a €4.2 million Series A investment round with ALTA Life Science, HealthEquity and Business Angels, which will allow the company to reach clinical trials in the first quarter of 2020. The funds will be used to complete the CMC (Chemistry, Manufacturing and Control) development of the first Omomyc-based product and obtain GLP (Good Laboratory Practice) stocks to be administered to patients, and advance the preclinical validation of new products such as TMTP1-Omomyc. A Series B investment round is planned for 2018, which should raise €15 million to finance clinical trials for two or more diseases. Economically, the demonstration that ibrutinib is effective against this disease would open up a new market worldwide, with around 338,000 cases of pancreatic cancer diagnosed annually10 (2012 data). However, our results suggest that the impact of ibrutinib could go much further, as its use could be extended to other solid tumors such as breast or melanoma, and potentially to other fibrotic diseases unrelated to cancer1. We will continue working on this line of research to test these hypotheses which, if confirmed, could expand the range of pathologies susceptible to being treated with ibrutinib, further enhancing its commercialization.

Doctoral Thesis; Industrial Interest; Commercial Interest; Ibrutinib (Imbruvica); Pancreatic Cancer Treatment; Omomyc; Breast Cancer Treatment; Other Pathologies; Marketed Drug; BTK Inhibitor; B Lymphocytes; Immune System Cells; Hematological Cancers; Leukemias; Lymphomas; Chronic Lymphocytic Leukemia; Mantle Cell Lymphoma; Waldenström Macroglobulinemia; First-line Treatment; Pharmacyclics LLC; AbbVie; Solid Tumors; Mast Cells; Tumor Growth Reduction; Mouse Models; Tumor Stroma; Fibrotic Layer; Collagen Fibers; Protective Barrier; Conventional Drugs; Chemotherapy Penetration; Increased Survival; Anti-fibrotic Property; Patent Registration; PCT/US2015/063475; Myc Family Inhibition; Conventional Therapies; Extraordinary Efficacy; Tumor Mutations; Mild Side Effects; Reversible Side Effects; No Resistance Detected; Preclinical Models; Transgene; Human Cells in Culture; Transgenic Mice; Multiple Cancer Types; Metastatic Breast Cancer; Proof of Concept; Peptomyc S.L.; Spin-off; Drug Administration; VHIO.