2023-12-015 + 2021-08-009 - ALL-BePrecise-2 - Precision medicine in infant t(4;11) pro-B-ALL: targeting the novel biomarker HDAC7

ALL-BePrecise-2

2023-12-015 + 2021-08-009

HDAC7 as a novel biomarker that determines prognosis in infants that that present MLL-AF4 rearrangement (t(4;11) pro-B-ALL), due to a translocation between chromosomes 4 and 11.

The research group has identified HDAC7 as a relevant marker of patient-associated survival, with potential to define prognosis in distinct types of B cell hematological diseases. The asset in development arises from the fusion of basic knowledge, pre-clinical and clinical data, presenting an evident translational orientation. The results obtained will be of great scientific relevance and may allow the development of new precision therapies, aiming to trigger HDAC7 biomarker expression in B-cell associated malignancies. Even though, we center our studies in an ultra-rare pathology such as t(4;11) infant pro-B-ALL. The project executed herewith will set a precedent in the development of treatments for other diseases involving HDAC7, such as DLBCL. Principal and direct beneficiaries will be a subgroup of infants with t(4;11) pro-B-ALL refractory to current treatments that, in most of the cases do not survive more than their first year of life. Additionally, secondary beneficiaries would be clinicians, who would obtain better informed clinical decision making through HDAC7 expression levels and new treatments for this pathology. Finally, adult patients suffering from pro-B-ALL and DLBCL will also benefit from the findings of this project. In fact, the project has already had a social impact, receiving funding from the sales of a charity book (a campaign from Josep Carreras Foundation), an original idea from the family of a pro-B-ALL-diagnosed infant. The performance of this project complies with the provisions of international principles and current regulations that are applicable in terms of bioethics, animal experimentation, biosecurity, biological safety, environmental protection, and data protection, and respects the fundamental principles established in the Declaration of Helsinki (World Medical Assembly), in the Council of Europe Convention on human rights and biomedicine and in the Unesco Universal Declaration on the human genome and the human rights. The main objectives of the Governance at the IJC are: Establish an efficient and sustainable management and organization in accordance with the objectives of the group; Guarantee the maximum return to society of the results of the research in the form of impact on health, knowledge and economic progress; Establish interdisciplinary collaborations with groups from other prestigious national and international centers.

Infants suffering from t(4;11) pro-B-ALL have no other available treatment with an adverse outcome of 35% of survival. It is proposed herein to offer a novel treatment based on the modulation of HDAC7, that has become a promising target to offer an opportunity to these hopeless patients and their families and to determine patients' prognosis and follow up through the assessment of novel biomarker HDAC7 levels (companion diagnostic kit). Even in the case that these new treatments would not arrive to patients, the process itself would generate both scientific and clinical knowledge, social awareness and impact that could lead to research on new treatments and overall quality of life improvement for infants. Economically, pharma companies marketing this therapy would not benefit from direct sales if the focus is only in infant pro-B-ALL, as this is an ultra-rare pathology but, they would get regulatory benefits such as a fast track to market (e.g. “orphan drug designation”). More importantly, experimental developments related to this discovery could lead to new treatments for related haematological disorders, widening the scope of targeted diseases and beneficiaries.

t(4;11) pro-B-ALL is a highly aggressive subtype of infant pro-B-ALL associated with a survival rate of 35%, chemoresistance to current treatment and commonly relapse. HDAC7 has been described as a novel biomarker that determines prognosis in this ultra-rare disease. The loss of HDAC7 expression is associated with the poor outcome of these patients who, due to their short age, are normally excluded from clinical trials, rendering them to no alternative treatment rather than compassionate use. At the moment, there are no other therapeutic options available for these highly vulnerable infants. We are developing a novel small molecule-based combinatorial therapy that precisely induces HDAC7 expression in t(4;11) pro-B-ALL cells, consisting of a Menin inhibitor (MI-538) and a class I selective HDAC inhibitor (Chidamide). We have demostrated that the addition of these drugs to chemotherapy regimen (VxL) impairs leukemogenic potential both in vitro and in vivo.

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The business model envisioned was through a license, expected to be executed before the patent enters to national phases (June 2024).

New therapeutic approaches are needed to be implemented in the clinical practice, which improve patients’ survival and life quality. In particular, a precise therapy that induces HDAC7 biomarker expression to increase chemotherapy sensitivity and improve patient prognosis.

Besides infant t(4;11) pro-B-ALL, we have proven that it is extendable to adult pro-B-ALL and other haematological malignancies such as DLBCL, which also harbour low HDAC7 expression.

Regulatory preclinical prior to FiH: 900.000 €

1. Pre-clinical validation (ongoing) 2. Regulatory Roadmap (done) 3. Clinical Trials 4. Marketing Approval

New therapeutic approach to improve survival and first treatment designed for HDAC7 induction. Use of small molecules instead of conventional chemotherapy. Novel classification of hematologic malignancies into HDAC7+ and HDAC7- cancers to identify those patients with improved outcome chances (HDAC7+), oppositely to those with low presence of HDAC7, that harbor a poorer prognosis. Further development of an IVD kit. Specific induction of HDAC7 shifting from current non-specific treatments in poor prognostic patients towards an individualized and precise therapy.

Objective 1. In vivo validation of MI-538 and Chidamide combined therapy. Objective 2. Preclinical regulatory assays for HDAC7-inducing compounds. Objective 3. Execution of the business development and transfer plan.

PCT patent abandoned

The IP was 100% IJC- Althoug the project is abandoned, the team is still in international collaborations to work scientifically in the HDAC7 target and pro-B ALL and other hematologic and pediatric diseases

Therefore, the results obtained will be of great scientific and clinic relevance and may allow the development of new precision therapies. Even though the project focuses on an ultra-rare pathology, it will set a precedent in the development of treatments for other diseases involving HDAC7. Thus, the value proposition suggested here is that treating patients with t(4;11) pro-B-ALL will not promote economic growth by itself, but expanding the portfolio with new indications will.