Page 112 - Read Online

Offin et al. J Cancer Metastasis Treat 2023;9:21 https://dx.doi.org/10.20517/2394-4722.2022.140 Page 9 of 16

regulates the HIPPO pathway by negatively regulating transcriptional co-activators YAP and TAZ through
the E3 ubiquitin ligase CRL4 DCAF1 ; YAP and TAZ disinhibition results in an oncogenic cascade predisposing
to the development of DPM [106-109] . Due to the genomic enrichment of NF2 alterations in DPM
(19%-25%) [8,22] , several trials evaluating this pathway in patients with NF2-altered DPM have been conducted
or are underway [Table 5].

The oral small-molecule focal adhesion kinase (FAK) TKI defactinib has been investigated in multiple solid
tumor types, including ovarian, colorectal, pancreatic, and lung cancers . Defactinib selectively kills
[112]
Merlin-expressing cells through a FAK-Merlin synthetic lethal pathway. In a large, global, randomized
phase II trial, 344 patients with DPM and with disease control after 4 cycles of first-line platinum/
pemetrexed-based chemotherapy were assigned to receive either defactinib or placebo; Unfortunately,
[110]
neither PFS nor OS was improved with defactinib . Trials evaluating other inhibitors of this pathway are
underway, including (1) Nedd8-activating enzyme (NAE) inhibitors which result in decreased formation of
CRL4 DCAF1 (NCT03319537); and (2) YAP/TEAD inhibitors (NCT04857372).

CDKN2, p16, MTAP: Co-deletion of the CDKN2A and methylthioadenosine phosphorylase (MTAP) genes is
notably enriched in 28%-49% of DPM [8,16,22,113,114] . The proximity of the CDKN2A gene on chromosome 9p21
to MTAP predisposes the loss of both genes with the loss of one allele [115,116] . CDKN2A encodes p16INK4a
and p14AR, important cell cycle modulators which regulate cyclin-dependent kinases (CDKs) [117-119] .
Enrichment of these alterations poses distinct mechanistic vulnerabilities under investigation: (1) Protein
arginine methyltransferase 5 (PRMT5); and (2) Cyclin-dependent kinase (CDK) inhibition [Table 6].

In vitro, PRMT5 inhibition has been evaluated as a potential therapy against MTAP-deficient cancers,
including DPM . Early phase clinical trials of the safety and possible roles of PRMT5 inhibitors in solid
[121]
tumors, including DPM, are currently underway (NCT05245500, NCT05275478, NCT04794699). Direct
CDK4/6 inhibitors have synthetic lethality in DPM [122,123] and are under active investigation. In the single-
arm, phase 2, MiST 2 trial, 26 patients with p16INK4A-deficient DPM whose disease had progressed after
platinum-based chemotherapy received the oral CDK4/6 inhibitor, abemaciclib. The study met its primary
endpoint, with a DCR of 54% at 12 weeks, tumor volume reductions in 80% of evaluable patients, and four
[120]
patients who achieved a partial response . These results are encouraging evidence of possible antitumor
effects, but a larger randomized trial and further refinement of possible biomarkers are needed to determine
any possible place in our current clinical practice [124,125] .

V-domain Ig suppressor T cell activation (VISTA): VISTA is a negative immune checkpoint regulator of
myeloid and T cell function with high levels of expression in DPM (85%) . In vivo studies suggest anti-
[17]
VISTA antibodies have promising antitumor activity [16,17,126] . With the integration of 1L immunotherapy into
the treatment paradigms for DPM , exploration of later-line treatment options to improve response and/
[18]
or rechallenge to immunotherapy is needed. A phase 1 study of CA-170 (small molecule inhibitor of PD-L1
and VISTA) in patients with previously treated advanced solid tumors and lymphomas exhibited an
[127]
acceptable toxicity profile and is currently under development. The VISTA inhibitor CI-8993 is currently
[128]
under investigation in a phase I study evaluating the safety and activity of this antibody in patients with
previously treated advanced solid tumors (NCT04475523).

Argininosuccinate synthetase 1 (ASS1): ASS1 is a key enzyme in the urea cycle required for the formation
of arginine, and ASS1-deficiency has been implicated in tumorigenesis by supporting cellular proliferation
and pyrimidine synthesis [129,130] . Certain solid tumors, including nearly two-thirds of DPM, have inherent
[131]
enrichment for ASS1-deficiency and mechanistically lend themselves to therapeutic exploitation with