PTC-028 / PTC Therap - LARVOL DELTA

Pharmacologic inhibition of BMI1 exerts antitumor effects against MYCN-amplified neuroblastoma, with activation of the p53 pathway. (PubMed, Sci Rep) - "In our present study, the BMI1 inhibitors PTC-028 and PTC-209 exhibited selective antitumor activity against MYCN-amplified neuroblastoma. Significantly, PTC-028 also exhibited antitumor efficacy in a mouse xenograft model of human neuroblastoma. These results suggest that BMI1 inhibitors, particularly PTC-028, are promising therapeutic agents for the management of aggressive MYCN-amplified neuroblastomas."

Journal • Neuroblastoma • Oncology • Solid Tumor • BCL2 • BMI1 • MCL1 • MYCN

Targeting BMI-1 to deplete antibody-secreting cells in autoimmunity. (PubMed, Clin Transl Immunology) - "PTC-028 was also efficacious in reducing ex vivo plasma cell survival from both Sjögren's syndrome patients and age-matched healthy donors. These data provide evidence that inhibiting BMI-1 can deplete ASC in a variety of contexts and thus BMI-1 is a viable therapeutic target for antibody-mediated autoimmune diseases."

Journal • Immunology • Inflammatory Arthritis • Lupus • Sjogren's Syndrome • Systemic Lupus Erythematosus • BMI1 • LYN

BMI1 Regulates Proliferation of Human Late-Stage Erythroid Progenitors (ASH 2022) - "In support of this hypothesis, treatment of human CD34+ cell erythroid cultures with the BMI1 inhibitors, PTC209 or PTC028, reduced late-stage (EP3 and EP4), but not immature (EP1 or EP2), erythroid progenitor numbers. Interestingly, SRE proliferation was significantly, but not completely, rescued by the addition of exogenous lipids, highlighting the importance of cholesterol metabolism in human SRE proliferation. These findings, taken together, support the hypothesis that BMI1 regulates erythroid self-renewal through several mechanisms including the cell cycle and cholesterol biosynthesis."

BMI1 • CD34

[VIRTUAL] Efficacy of Tubulin Polymerization Inhibitor in Myelodysplastic Syndrome (ASH 2020) - "The first approved tubulin binding agent by the FDA was vincristine, which has been clinically used to treat multiple types of cancers, particularly hematological malignancies...PTC-028 synergized with hypomethylating agents, such as decitabine and azacitidine, to inhibit the growth and induce apoptosis of MDS cells...In contrast, polymerized microtubules increased in cells treated with paclitaxel, which stabilizes microtubules against depolymerization... Our data reveal a possible chemotherapeutic strategy for PTC-028 and PTC-596 in MDS by disruption of microtubule dynamics as a single agent and in combination with hypomethylating agents. The present study provides a preclinical framework for the clinical evaluation of this promising therapeutic approach to improve outcomes in MDS patients."

Clinical • Hematological Disorders • Hematological Malignancies • Myelodysplastic Syndrome • Oncology • Transplantation • CASP3 • CD34

Epigenetic regulator BMI1 promotes alveolar rhabdomyosarcoma proliferation and constitutes a novel therapeutic target. (PubMed, Mol Oncol) - "We depleted BMI1 using RNAi and inhibitors (PTC-209 and PTC-028) and found that this leads to a decrease in cell growth/increase in apoptosis in vitro, and delays tumor growth in vivo. Our data suggest that BMI1 inhibition activates the Hippo pathway via phosphorylation of LATS1/2 and subsequent reduction in YAP levels and YAP/TAZ target genes. These results identify BMI1 as a potential therapeutic vulnerability in ARMS and warrant further investigation of BMI1 in ARMS and other sarcomas."

Journal • Oncology • Pediatrics • Rhabdomyosarcoma • Sarcoma • Soft Tissue Sarcoma • Solid Tumor

Efficacy of the Novel Tubulin Polymerization Inhibitor PTC-028 for Myelodysplastic Syndrome. (PubMed, Cancer Sci) - "The novel small molecule PTC596 directly binds tubulin, inhibits microtubule polymerization, down-regulates MCL-1, and induces p53-independent apoptosis in acute myeloid leukemia cells...PTC-028 synergized with hypomethylating agents, such as decitabine and azacitidine, to inhibit growth and induce apoptosis in MDS cells...PTC-028 prolonged the survival of mice in xenograft models. The present results suggest a chemotherapeutic strategy for MDS through the disruption of microtubule dynamics in combination with DNA hypomethylating agents."

Clinical • Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • Solid Tumor • MCL1

Senescence Induced by BMI1 Inhibition Is a Therapeutic Vulnerability in H3K27M-Mutant DIPG. (PubMed, Cell Rep) - "Prolonged BMI1 inhibition induces a senescence-associated secretory phenotype, which promotes tumor recurrence. Clearance of senescent cells using BH3 protein mimetics co-operates with BMI1 inhibition to enhance tumor cell killing in vivo."

Journal • Diffuse Intrinsic Pontine Glioma • Glioma • Oncology • Solid Tumor • BMI1

BMI1 IS A THERAPEUTIC TARGET IN RHABDOMYOSARCOMA (ASPHO 2020) - "We then utilized two small molecule inhibitors, PTC-209 and PTC-028, to obtain IC50s in these cell lines and determined effects on cell proliferation and apoptosis in vitro and in vivo... BMI1 supports proliferation and survival in in vitro and in vivo models of FP-RMS. Inhibition of BMI1 decreases cell proliferation, increases apoptosis, and additionally promotes activation of the tumor suppressive Hippo pathway. Currently, we are further investigating the molecular mechanisms by which BMI1 promotes FP-RMS aggression."

BMI1 • FOXO1

The anti-mitotic agents PTC-028 and PTC596 display potent activity in pre-clinical models of multiple myeloma but challenge the role of BMI-1 as an essential tumour gene. (PubMed, Br J Haematol) - "Moreover, we observed a complete eradication of MM after PTC596 treatment in the 5TGM.1 in vivo model and define epigenetic compounds and B cell leukaemia/lymphoma 2 homology domain 3 (BH3) mimetics as promising combination partners. These results bring into question the postulated role of BMI-1 as an essential MM gene and confirm BMI-1 modulators as potent anti-mitotic agents with encouraging pre-clinical activity that supports their rapid translation into clinical trials."

Journal • BMI1

Inhibition of BMI1, a therapeutic approach in endometrial cancer. (PubMed, Mol Cancer Ther) - "In an aggressive uterine carcinosarcoma xenograft model, single-agent PTC-028 significantly delayed tumor growth and increased tumor doubling time compared with the standard carboplatin/paclitaxel therapy. In an aggressive uterine carcinosarcoma xenograft model, single agent PTC-028 significantly delayed tumor growth and increased tumor doubling time compared to the standard carboplatin/paclitaxel therapy. Therefore, anti-BMI1 strategies may represent a promising targeted approach in patients with advanced or recurrent endometrial cancer, a population where treatment options are limited."

Journal

The first-in-class BMI-1 modulators PTC-028 and PTC596 display potent activity in pre-clinical models of multiple myeloma (IMW 2019) - "This remarkable activity was confirmed in an independent experiment demonstrating similar potency (i.e. no detectable MM cells post PTC596 treatment). Taken together, these results bring into question the postulated role of BMI-1 as an essential MM gene and reveal BMI-1 modulators as potent anti-mitotic agents with encouraging pre-clinical activity that supports their rapid translation into clinical trials."

PARP Biomarker

THE FIRST-IN-CLASS, ORALLY AVAILABLE BMI-1 MODULATORS PTC-028 AND PTC596 DISPLAY POTENT ACTIVITY IN PRE-CLINICAL MODELS OF MULTIPLE MYELOMA (EHA 2019) - "Moreover, our data suggest that BMI-1 levels could serve as predictive marker, reveal BMI-1 modulators as potent anti-mitotic agents that target key MM genes (e.g. MYC) and show strong synergism with experimental anti-MM drugs. These results strongly support the clinical evaluation of this novel drug class in myeloma."

IO Biomarker • PARP Biomarker

BMI1 is a therapeutic target in recurrent medulloblastoma. (PubMed, Oncogene) - "Strikingly, serial in vivo re-transplantation assays demonstrated a marked reduction in tumor initiation ability of recurrent MB cells upon re-transplantation of PTC-028-treated cells into secondary recipient mouse brains. As Group 3 MB is often metastatic and uniformly fatal at recurrence, with no current or planned trials of targeted therapy, an efficacious targeted agent would be rapidly transitioned to clinical trials."

Journal

Targeting epigenetic regulator BMI-1 in alveolar rhabdomyosarcoma (AACR 2019) - "BMI1 supports proliferation and survival in cell line models of ARMS. Both chemical and pharmacologic inhibition of BMI1 led to striking decreases in cell proliferation. Currently, we are further investigating the molecular impact of BMI1 inhibition, with plans to investigate its effectiveness within an in vivo ARMS model."

Therapeutic targeting of stem cell self-renewal in childhood medulloblastoma: Strategies for blocking recurrence (AACR 2019) - "Characterization and therapeutic targeting of self-renewal mechanisms unique to MB BTICs may provide an opportunity to limit treatment-resistant stem cell populations from driving patient relapse in recurrent Group 3 MB, a disease currently lacking any targeted therapies."

Clinical