Pexidartinib (PLX3397)

Colony stimulating factor-1 (CSF1) is a key cytokine involved in recruitment and activation of tissue macrophages, exerting these effects through binding to a high-affinity receptor tyrosine kinase, the cFMS/CSF1 receptor. Pexidartinib (PLX3397) is a CSF-1R inhibitor that can cross the blood–brain barrier.

In vitro: PLX3397 strongly dampened the systemic and local accumulation of macrophages driven by B16F10 melanomas, without affecting Gr-1+ myeloid derived suppressor cells [1].

In vivo: Wild-type C57 mice were orthotopically injected with GL261 cells and fed with PLX3397 compound. After 2 wks, tumors in the control group showed extensive microglia infiltration. In animals fed PLX3397, however, there was a substantial reduction in the number of Iba1- positive cells at the tumor [2].

Clinical trial: In a phase Ib trial, patients with advanced solid tumors are treated with weekly paclitaxel and escalating doses of oral PLX3397 to establish a RP2D of PLX3397. This study will support further development of the PLX3397-paclitaxel combination in the I-SPY-2 neoadjuvant breast cancer trial.

Reference:
[1] Sluijter M, van der Sluis TC, van der Velden PA, Versluis M, West BL, van der Burg SH, van Hall T.  Inhibition of CSF-1R supports T-cell mediated melanoma therapy. PLoS One. 2014 Aug 11;9(8):e104230.
[2] Coniglio SJ, Eugenin E, Dobrenis K, Stanley ER, West BL, Symons MH, Segall JE.  Microglial stimulation of glioblastoma invasion involves epidermal growth factor receptor (EGFR) and colony stimulating factor 1 receptor (CSF-1R) signaling. Mol Med. 2012 May 9;18:519-27.


The CSF1 receptor inhibitor pexidartinib (PLX3397) reduces tissue macrophage levels without affecting glucose homeostasis in mice.[Pubmed:30926949]

Int J Obes (Lond). 2019 Mar 29. pii: 10.1038/s41366-019-0355-7.

BACKGROUND AND OBJECTIVES: Excessive adipose tissue macrophage accumulation in obesity has been implicated in mediating inflammatory responses that impair glucose homeostasis and promote insulin resistance. Colony-stimulating factor 1 (CSF1) controls macrophage differentiation, and here we sought to determine the effect of a CSF1 receptor inhibitor, PLX3397, on adipose tissue macrophage levels and understand the impact on glucose homeostasis in mice. METHODS: A Ten-week-old mice were fed a chow or high-fat diet for 10 weeks and then treated with PLX3397 via oral gavage (50 mg/kg) every second day for 3 weeks, with subsequent monitoring of glucose tolerance, insulin sensitivity and assessment of adipose tissue immune cells. RESULTS: PLX3397 treatment substantially reduced macrophage numbers in adipose tissue of both chow and high-fat diet fed mice without affecting total myeloid cell levels. Despite this, PLX3397 did not greatly alter glucose homeostasis, did not affect high-fat diet-induced increases in visceral fat cytokine expression (Il-6 and Tnfa) and had limited effect on the phosphorylation of the stress kinases JNK and ERK and macrophage polarization. CONCLUSIONS: Our results indicate that macrophage infiltration of adipose tissue induced by a high-fat diet may not be the trigger for impairments in whole body glucose homeostasis, and that anti-CSF1 therapies are not likely to be useful as treatments for insulin resistance.

Tenosynovial giant cell tumor: case report of a patient effectively treated with pexidartinib (PLX3397) and review of the literature.[Pubmed:30002809]

Clin Sarcoma Res. 2018 Jul 10;8:14.

Background: Tenosynovial giant cell tumors (TGCTs) or giant cell tumors of tendon sheath are neoplasms that arise in the synovium. They can be categorized as nodular (localized) or diffuse type (D-TGCT). Historically, surgery has been the mainstay of therapy, but diffuse type disease recurs at a high rate and treatment often requires increasingly morbid procedures. Elucidation of the importance of the colony-stimulating factor (CSF1)/CSF1 receptor (CSF1R) pathway in the pathogenesis of this disease has created significant interest in targeting this pathway as a novel TGCT treatment approach. Pexidartinib, a selective tyrosine kinase inhibitor against CSF1R, showed an 83% disease control rate (52% with partial response and 31% with stable disease) in a recent phase 1 study of patients with TGCT. Case presentation: We present an illustrative example of a TGCT patient who would have required a morbid operation who derived considerable clinical benefit from pexidartinib treatment. Her tumor volume decreased by 48% after 4 months of treatment, and 55 months after starting treatment the patient exhibits continued disease stability with minimal clinical symptoms, and significant improvement in functional status. Conclusions: This case illustrates the effectiveness of systemic therapy in controlling a disease associated with high surgical morbidity. This approach may be especially useful in the treatment of extra-articular disease which often invades neurovascular bundles; as the effectiveness in metastatic disease is still unknown. In the future, systemic treatment for TGCT may be appropriate for the neoadjuvant setting to decrease disease burden prior to surgery with the aim of decreasing recurrence rates. However, properly designed prospective studies will need to be carried out to answer these questions.

Patient-reported Symptoms of Tenosynovial Giant Cell Tumors.[Pubmed:27041409]

Clin Ther. 2016 Apr;38(4):778-93.

PURPOSE: Tenosynovial giant cell tumor (TGCT), a rare locally aggressive neoplasm of the synovium of joints and tendon sheaths, is associated with joint destruction, inflammation, pain, and swelling, in part due to colony-stimulating factor 1 receptor-bearing macrophages recruited to the tumor by genetic elevation of colony-stimulating factor 1 activity. The most common treatment is surgery, although promising pharmacologic treatments are in development. Patient-reported outcome (PRO) instruments are critical end points in demonstrating the clinical relevance of standard oncologic outcome measures and the overall impact of novel pharmacologic therapies in nonmalignant neoplastic conditions such as TGCT. The content validity of PROs relevant to patients with TGCT has not been formally investigated, and instruments to evaluate such outcomes do not exist for this condition. METHODS: PRO instruments of potential relevance were evaluated by using a literature review and by clinical and PRO experts. Patients with TGCT were recruited through clinical sites and the Internet for participation in qualitative research interviews to identify predominant symptoms and to test the relevance and content validity of several PRO measures. Select PRO measures were included in a Phase I clinical trial, and preliminary results of the PRO end points are reported descriptively. FINDINGS: Of the 22 subjects who participated in qualitative interviews, 73% were female, and their mean age was 42.5 years (range, 27-56 years). The TGCTs (19 diffuse and 3 localized) were located in the knee (n = 15), hip (n = 3), ankle (n = 2), elbow (n = 1), and forearm (n = 1). The most common symptoms cited were pain (82%), swelling (86%), stiffness (73%), reduced range of motion (64%), and joint instability (64%), which were consistent with clinical expert input and with the content of instruments chosen by PRO experts. The worst pain numeric rating scale, Patient Reported Outcomes Measurement Information System physical functioning items, and the Western Ontario and McMaster Universities Osteoarthritis Index, as well as a worst stiffness numeric rating scale developed for TGCT, were confirmed as meaningful measures of TGCT patient symptoms and were well understood in qualitative interviews. Results from the Phase I trial showed trends of improvement in both pain and stiffness over time. IMPLICATIONS: This study is the first to gather information directly from patients with TGCT regarding their symptom experiences. Pain, stiffness, and physical functioning are important treatment outcomes in patients with TGCT. We have identified content-valid PRO measures of these concepts, which are included in an ongoing Phase III TGCT clinical trial with Pexidartinib (PLX3397) (NCT02371369).

Pexidartinib (PLX-3397) is a potent, orally active, selective, and ATP-competitive colony stimulating factor 1 receptor (CSF1R or M-CSFR) and c-Kit inhibitor, with IC50s of 20 and 10 nM, respectively. Pexidartinib (PLX-3397) exhibits 10- to 100-fold selectivity for c-Kit and CSF1R over other related kinases. Pexidartinib (PLX-3397) induces cell apoptosis and has anti-tumor activity.

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