A dual PAM inhibitor to overcome limitations of first generation drugs
PAM (PI3K/AKT/mTOR) is one of the most important cell signaling routes. It involves three main factors (also known as molecular nodes): phosphatidylinositol-3-kinases (PI3K), protein kinase B (PKB or AKT) and mammalian target of rapamycin (mTOR), all of which exist in different isoforms.
This signaling pathway is central to a number of cell functions including proliferation, survival, motility, metabolism and angiogenesis [1, 2]. Physiologically, PAM is activated in response to an extracellular signal (growth factor, hormone...) captured by a cell surface radar: a receptor tyrosine kinase. Once activated, it triggers a cascade of molecular handshakes from the surface to the nucleus of the cell in less than a second:
- PI3K (an enzyme, called a kinase, that activates certain molecules by adding a phosphate group that it retrieves from the energy transporter ATP) first converts the membrane phospholipid PIP2 to PIP3;
- The kinases PDK1 and AKT then join the cell membrane where the former activates the latter;
- Once phosphorylated, AKT in turn activates the mTORC1 complex located in the heart of the cell;
- Finally, p70S6K activates the genes that will ensure a cellular response in accordance with the signal received (proliferation, suicide...).
Given the plethora of intracellular functions it is involved in, the PAM pathway is unsurprisingly linked to cancer development, among other diseases. It is one of the most frequently altered pathways in all human cancers . It is overexpressed in gastric cancers , various lymphomas [5,6], and nearly half of breast cancers  and involved in resistance to various cancer therapies .
In August 2021, Diaccurate has entered into an exclusive global license agreement with Merck Healthcare KGaA for M2698, now DIACC3010, a dual PAM inhibitor. This new phase II-ready sole-in-class drug candidate is an oral small chemical molecule that can cross the blood-brain barrier, a rare property among cancer drugs, as illustrated by the very low survival rate of patients with brain metastases .
First and second generation PAM inhibitors effectively block tumor progression, but their scope is still limited
Approved by the FDA in 2008 for the treatment of advanced renal cancer , the mTOR inhibitor temsirolimus (torisel®, Pfizer) was the first PAM inhibitor used in oncology. Since then, other inhibitors (targeting mainly mTOR and PI3K) have been approved but most of these products are still undergoing preclinical and clinical development.
PAM inhibitors are typically very effective in blocking the proliferation of cancer cells in culture, have strong anti-tumor activity in animals but have yet to confirm their clinical potential.
Toxicity is their primary Achilles heel. The PAM pathway is one of the major cell signaling pathways and affects many downstream molecules.
As a consequence, PAM inhibitors often have limited efficacy and significant toxicity, which further reduces their therapeutic window.
Today, second generation inhibitors, which target certain isoforms or molecules positioned downstream of the PAM pathway, are both more specific and less toxic . These new molecules could also overcome resistance to certain cancer drugs and act in synergy with them. Preclinical studies have shown that certain second-generation inhibitors overcome resistance to anti-estrogens and trastuzumab (Herceptin®, Roche) in hormone-dependent ER+  or overexpressing HER2+ breast cancer [13,14], as well as acting synergistically with alkylating agents or antimitotics such as taxanes in triple-negative breast cancer [15,16,17].
A PAM pathway inhibitor with unique features and the ability to cross the blood-brain barrier
The mechanism of action of DIACC3010 gives it a series of advantages over first and second generation PAM pathway inhibitors, both in terms of activity and safety.
DIACC3010 blocks p70S6K, which potently inhibits the PAM pathway, but also two of the three AKT isoforms (AKT1 and AKT 3), which suppresses any excess activated AKT that might result from a possible negative feedback loop. This dual mode of action should significantly improve the efficacy of the PAM therapeutic approach.
AKT2 is specifically involved in the insulin-dependent translocation of the glucose transporter type 4 (GLUT4). In mice, its inactivation triggers hyperglycemia, an adverse effect commonly observed in patients treated with PAM inhibitors and most likely resulting from AKT2 inhibition. DIACC3010 is not expected to induce hyperglycemia since it bypasses AKT2. Therefore, its safety profile is also more favorable.
Figure 1: DIACC3010 acts simultaneously on two molecular nodes of the PAM pathway: AKT and p70S6K
Phase 1 clinical trial successfully completed
Solid preclinical studies with this compound strongly supported the clinical development of DIACC3010, for which a phase 1 trial has been completed in patients with advanced cancer who failed standard therapies . DIACC3010 was well tolerated in monotherapy and potential biomarkers of pharmacological activity were seen in peripheral blood mononuclear cells and tumor tissues. Combined with trastuzumab or tamoxifen, DIACC3010 also demonstrated early signals of antitumor activity in patients with advanced breast cancer resistant to multiple standard therapies.
The clinical development strategy for DIACC3010 is based on extensive preclinical data generated by Merck Healthcare KGaA in various tumor models, the rationale for targeting the PAM pathway in cancers where it is most deregulated, clinical data obtained with DIACC3010 in the Phase 1 trial (solid tumors, including breast cancer), the state of the competition and historical results of other inhibitors of the pathway, as well as the understanding of treatment algorithms and medical need in the various indications.
The clinical development of DIACC3010 is structured around two main studies.
- A Phase I/II trial in solid tumors
As the combination of DIACC3010 with paclitaxel has never been studied in humans before, a short first part as a Phase I dose escalation study will first determine the dose of DIACC3010 that will be used in the second part of the study in an intermittent administration schedule.
The phase II part of the study will be conducted in three independent parallel cohorts (inclusion criteria will include patients with brain metastases unlike most other clinical studies):
- Cohort 1: first-line PD-L1 negative TNBC in combination with paclitaxel ;
- Cohort 2: second-line HER2-negative gastric cancer in combination with paclitaxel;
- Cohort 3: third-line gastric cancer monotherapy.
The start of this trial is planned for the second half of 2022 (Phase I) followed by cohort expansions mid-2023. The protocol may include (independently for each cohort), interim futility analyses, the results of which could be available between early and mid-2024 (depending on the cohort). Depending on the complete results of each Phase II cohort, pivotal registration studies could start in early 2025.
- A phase II trial in relapsed or refractory aggressive lymphomas
For this trial, Diaccurate is planning to work in collaboration with physicians who are experts in the field and who would therefore be sponsors of the trial. Indications of choice include DLGCB, PTCL and other aggressive lymphomas, while the protocol remains to be developed with partners.
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