AUTHORS
Christel NAVARRO, Apostolia M. TSIMBERIDOU, Cécile BOUGERET, Dominique BRIDON, Elsa BORGHI, Hélène SICARD
ABSTRACT
Background: In resistant breast cancer, ribosomal protein S6 kinase (S6K) is a key regulator of estrogen receptor (ER) function, and its high expression is associated with poor clinical outcomes in breast cancer (BC). Recent data have demonstrated that S6K is involved in resistance to CDK4/6 inhibitors in metastatic BC (MBC). DIACC3010 (formerly M2698) is an oral brain-penetrant potent inhibitor of S6K. By design, DIACC3010 also selectively inhibits AKT1 and AKT3, while sparing AKT2. DIACC3010 was previously evaluated in a phase 1 trial (NCT01971515). We performed exploratory correlative analyses of the phase 1 trial in ER+ HER2-negative MBC patients in addition to nonclinical experiments to evaluate its role in the CDK4/6 and endocrine therapy (ET) resistant setting.
METHODS
DIACC3010 was evaluated as monotherapy, or combined with either trastuzumab or tamoxifen, in a multicenter phase 1 trial that accrued 101 patients with advanced/refractory resistant breast cancer (1). The current analysis focused on patients with ER+ HER2-negative MBC and aimed to explore the efficacy of DIACC3010 according to ESR1 mutational status. DIACC3010 was also evaluated patient-derived xenograft (PDX) mouse models, in monotherapy and combined with tamoxifen or palbociclib, and in xenograft models alone and in combination with elacestrant or abemaciclib.
RESULTS
Twenty patients were evaluable at baseline for their tumor mutational status and included in the analysis. Median age was 60 years and median number of prior lines of therapy was 5.5. Twelve of 20 (60%) patients had received prior treatment with CDK4/6 inhibitors. Nine of 20 patients (45%) had ESR1 mutations, of whom 4 had received CDK4/6 inhibitor. Median progression free survival was 5.6 months in patients with ESR1 mutations, and 2.6 months in patients with ESR1 wild-type tumors. Among the 13 ER+ BC PDX models evaluated, 12 provided interpretable results. The combination of DIACC3010 with tamoxifen or palbociclib induced respectively 10/12 (83%) and 11/12 (92%) significant tumor growth control in PDX models, of which 42% were resistant to tamoxifen and 50% were resistant to palbociclib. The combination of DIACC3010 with elacestrant or abemaciclib induced respectively 77% and 75% significant tumor growth control in MCF7 xenograft model. Furthermore, DIACC3010 monotherapy resulted in significant tumor growth control in 3/5 (60%) of the tamoxifen-resistant PDX models and 5/6 (83%) of the Palbociclib-resistant PDX models.
Patients (N = 101) with advanced resistant breast cancer (relapsed/refractory metastatic solid tumors) were enrolled in a large Phase 1 trial (1). The trial comprised DIACC3010 dose-escalation in monotherapy followed by multiple cohort expansions (1).
The current analysis focuses on the combination cohort of DIACC3010 and tamoxifen in resistant breast cancer (refractory ER+ HER2- metastatic cancer).
Prior anticancer therapies included palbociclib, everolimus, fulvestrant and other endocrine therapies.
DIACC3010 alone and in combination with tamoxifen or palbociclib was tested in a panel of 12 breast cancer Patient-Derived Xenograft (PDX) models.
Six- to 12-week-old female athymic Nude mice (n=4 mice per group) were implanted subcutaneously (SC) with 70 mg tumor fragment.
Dosing regimen, with all drugs administered per os (PO) and daily were:
– DIACC3010 25 mg/kg & tamoxifen 3 mg/kg, n=10 models (#)
– DIACC3010 25 mg/kg & tamoxifen 5 mg/kg, n=2 models
– DIACC3010 30 mg/kg & tamoxifen 1 mg/kg, n=1 model
– DIACC3010 25 mg/kg & palbociclib 40 mg/kg, n=9 models
– DIACC3010 25 mg/kg & palbociclib 75 mg/kg, n=3 models
– DIACC3010 30 mg/kg & palbociclib 75 mg/kg, n=1 model (##)
Five out of 12 PDX models were found resistant to tamoxifen (42%) and 6 were found resistant to palbociclib (50%) (both drugs had no anti-tumor activity as compared to vehicle).
DIACC3010 alone and in combination with elacestrant or abemaciclib were tested in MCF7 human breast cancer (ATCC purchased) xenograft in Nude mice.
D-1: Mice were implanted with 0.18 mg b-estradiol containing pellets.
D0: mice were injected with 5.106 cells in 200 μl PBS:Matrigel (50:50).
Treatments started on D19 (tumor vol. ~100 mm3) with all drugs administered PO once daily for 21 days (n=8 mice/group), with the doses presented in Fig. 4.
DIACC3010 induced 71% MCF7 tumor growth inhibition as compared to vehicle, more potently than elacestrant (47%) (Fig. 4.A) and as efficiently as abemaciclib (67%) (Fig. 4.B).
CONCLUSION
These exploratory analyses from the phase 1 trial, along with nonclinical efficacy in monotherapy and in combination with standard treatments in various models of breast cancer, support further clinical development of DIACC3010 in ER+ HER2- metastatic or resistant breast cancer.
A randomized Phase 2/3 study in combination with endocrine therapy will be conducted in the near future.
REFERENCES
1. AM Tsimberidou et al, J Hematol Oncol 2021 14(1):127
2. M Artemenko et al, Cancer Letters 2022 535(21):5593
3. RL Yamnik et al, J Biol Chemistry 2009 284(10):6361
4. H. Mo et al, Mol Cancer 2022 21(1):171
Download the poster here: posterAACR 2023 – DIACC3010_final
