RMC-9945

C57BL/6J mice (syngeneic, liver metastases induced by AKTP mouse tumor organoid inoculation into spleen)^[1]

100 mg/kg (monotherapy); 100 mg/kg + DT 25 μg/kg (combination therapy)

p.o.; daily; 11 days (day 15 initiation); p.o.; daily; 7 days + i.p.; every other day; 2 weeks (day 21 initiation combination); p.o.; daily; 10 days + i.p.; daily; 6 days (day 14 initiation combination); p.o.; daily; 6 days (transcriptional analysis)

Reduced the number and size of liver metastatic nodules when treatment started at day 15, though many persisted as drug-tolerant lesions.
Exerted limited therapeutic activity when treatment started at day 21 or 25, with metastases continuing to grow and no significant reduction in metastatic burden.
Induced transcriptional reprogramming of metastases, depleting Emp1+ high-relapse cells and enriching Lgr5+ cancer stem cells, with a significant increase in Lgr5 mRNA-positive cells (P < 0.0001 for both day 21 and day 15 initiation).
Reduced liver nodule number by twofold with monotherapy starting at day 21.
Reduced metastasis size threefold when combined with DT-mediated Lgr5+ CSC ablation starting at day 21.
Arrested metastatic outgrowth when treatment started at day 14.
Reduced metastatic load 10- to 11-fold when combined with DT starting at day 14, compared with either monotherapy.
Significantly extended mouse survival when combined with DT starting at day 14, compared with vehicle, RMC-9945 alone, or DT alone (P < 0.0001 for all comparisons).

KPC (9-week-old; genetically engineered to carry KrasG12D and Tp53R172H mutations; autochthonous model with spontaneous progression from acinar-to-ductal metaplasia to pancreatic intraepithelial neoplasia to invasive PDAC)^[3]

100 mg/kg

p.o.; daily; 10 days

Significantly reduced the percentage area of preneoplastic tissue (PanIN and acinar-to-ductal metaplasia) compared to vehicle controls.
Markedly diminished phosphorylated extracellular signal-regulated kinase (pERK) staining after 3 days of treatment.
Increased staining for cleaved caspase 3 in residual PanIN lesions, indicating induction of apoptotic cell death.
Left amylase staining (an acinar cell marker) unchanged relative to controls.

KPC (7-week-old; genetically engineered to carry KrasG12D and Tp53R172H mutations; autochthonous model with spontaneous progression from acinar-to-ductal metaplasia to pancreatic intraepithelial neoplasia to invasive PDAC)^[3]

100 mg/kg

p.o.; daily; 28 days

Suppressed preneoplastic burden to an extent greater than or equivalent to 10 days of treatment; fully eliminated detectable preneoplasia in 2 of 5 animals.
Significantly delayed tumor onset (median age at tumor onset 162 days versus 83 days in vehicle controls; P < 0.0001).
Prolonged median overall survival by ~80 days (median age at death 200 days versus 120 days in vehicle controls; P < 0.0001).
Left size at diagnosis and growth rate of tumors that emerged after interception similar to vehicle control tumors; left overall survival measured from tumor detection comparable to controls.