2022-10-006 - Cancer TTLL11 - Targeting tumours through a novel mechanism of genome instability (SpinSTL)

Cancer TTLL11

2022-10-006

Efficient, reproducible, sensitive and affordable unprecedented technology for single cell epigenetic profiling. Affordable and comprehensive approach not requiring the usage of specific devices.

Health and Safety

Developing a safe and effective therapy against TNBC will have an obvious positive impact on the patients, their families and the health system, as to date the prognostic of those patients is dimaying. Moreover, many other patients lack effective targeted therapies for their tumours, or become resitant to them (as to chemotherapy), not only in TNBC. Although one cannot deny that developments in the cancer field are enormous, and new and better treatments are constantly approved, there will always be a need to identify new safe and effective therapies for niche indications. Identifying these will be a challenge, and in the meantime we will keep a close look on the therapeutic developments for TNBC as they arise. in this respect, our close collaboration with clinitians at VHIR is key as it is our mentor under the CaixaImpulse grant (that has great expertise in the development of diagnostic and therapies for breast cancer), and in due time we plan to expand the network of clinical collaborators for other indications of potential interest (e.g lung, colon and uterus). In the loner run, if our developments successful, we expect a significant impact also for our ecosystem from licensing and/or spinning-off.

Breast cancer (BC) is currently the most common cancer globally, and one of the leading causes of cancer-related death in women. Triple negative breast tumours (TNBC, which account for 15–20% of all diagnosed BC) are particularly aggressive molecular subtypes of BC associated with early recurrence, high rate of metastasis, and poor clinical outcome. Despite recent approvals of drugs to treat TNBC (Trodelvy, olaparib and Keytruda), systemic chemotherapy including taxanes and other microtubule (MT) targeting agents (MTAs) is often the only viable option to reduce and/or prevent tumor progression and metastasis for many early-stage and advanced or relapsed TNBC patients. Taxanes and MTAs are compounds that directly bind to the MTs and stabilize them, impairing cancer cell division and proliferation. Their efficacy validates the general principle of targeting MT dynamics in cancer therapy. However, their clinical use is often limited by poor aqueous solubility, drug resistance and dose-limiting toxicities, as they target also healthy cells. Researchers at CRG have recently uncovered a mechanism that precisely defines homeostatic MT dynamics in mitosis by the enzyme TTLL (Zadra et al. Nat Commun.. 2022 Nov 21;13(1):7147). TTLL governs MT dynamics through polyglutamylation (polyQ) of the mitotic spindle. Faithful MT dynamics is required for chromosome segregation fidelity. 90% of tumours display chromosomal instability and aneuploidies as a result of chromosomal mis-segregation. Consistently, TTLL is systematically downregulated in human tumors but its activity is not compromised by mutations, suggesting that tumor cells may benefit from an increase in chromosome segregation errors, yet require a minimal level of TTLL activity to survive. Thus, compounds that inhibit TTLL, alone or in combination with (a priori low doses of) MT-stabilizing drugs like taxanes, can provide novel and effective therapies against TNBC by driving cancer cell death in a more targeted, safer and long-lasting manner (i.e. with potentially less resistance).

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To be defined. All options for now open.

There is a clear and urgent need for new therapies to treat TNBC that are safer and more effective than current chemotherapic regimes (administered alone or in combination). The need could be extended to other tumours/patients lacking effective targeted treatment options, or that have become resistant to previous treatments (since TTLL is downregulated in most human cancers, including lung, colon and ovarian).

TNBC and other tumour entities without effective treatment options at any stage. Although initial treatment will not be first line, our aim in the longer run would be to position TTLL-inhibiting drugs as first line treament in replacement of taxanes or other conventional chemotherapies (absent any effective targeted therapies).

Most immediate >500K (for drug development and preclinical validation).

Funding. KOLs/partners/collaborators with expertise to identify clinical needs beyond TNBC that could benefit most from targeting TTLL, as well as experts/partners/collaborators for drug development and validation in oncology.

.- Initial target validation succeeded (in vitro, and initiating in vivo) - Robust screening assay developed, ready for scale up, and first inhibitory compounds identified (from in silico screen) - Conditional KO strain validated (ES cells) and further developement ongoing

The novel target/MoA provide for a radically different approach to conventional cancer treatment, by inhibiting an already down-regulated cancer target instead of an overexpressed one. Our hypothesis is that reducing the levels of TTLL slightly should suffice to drive the cancer cells to die, while normal cells (where TTLL is not downregulated) would remain mostly unaffected (contrary to what taxanes and other MTAs do, as they do not discriminate). Initial proof of safety and efficacy has already been obained.

At this stage: 1.- Identifiying hit > lead compounds for preclinical validation, and protecting them/ensuring FTO 2.- Confirming in vivo that, actually, targeting MT dynamics specifically (though TTLL) is safer and more effective than doing it generally (using MTAs)

.- Additional target validation and MoA (benefit of targeting MT dynamics specifically vs generally, and against gold standard) in vitro and in vivo (in mice + expresion studies in patients' samples) - Identify hit compounds and most relevant clinical indication(s) - Hits performance in vitro and vivo, and hit-to lead optimization - Preclinical validation for the selected clinical indication - Additional patent protection and commercialization

First patent filed in EP and US, entitled INHIBITORS OF MICROTUBULE POLYGLUTAMYLATION IN MITOSIS FOR USE AS A MEDICAMENT (from WO2023089026). Further follow-up patents are foreseen to protect the specific compounds targeting TTLL, and potential indications.

Active collaborations with (i) Chemotargets (provided prioritized list of compouns from in silico screen, and continues to support the project in this regard), (ii) Mabel Loza (USC) for assay development and scaleup / compound screening and (iii) Santiago Ramón y Cajal (VHIR) for target validation in human samples of TNBC. With all we have agreements in place. Project for now under the control of CRG (but confidentiality obligations in some cases)

Patent: EP21383045.8