Neurotrophin Trk Receptors: New Targets for Cancer Therapy

Abstract

In the last few years, exciting reports have emerged regarding the role of the two types of neurotrophin receptors, p75 and Trks, not only in neurons, where they were discovered, but also in non-neural cells and, especially, in numerous cancers, including breast, lung, colon-rectum, pancreas, prostate, glioblastoma, neuroblastoma, myeloma, and lymphoid tumors. Traditionally, p75, activated by all neurotrophins and their precursors, is an inhibitor. In various cancers, however, activated p75 induces variable effects, from inhibition to stimulation of cell proliferation, dependent on their direct or coordinate/indirect mechanism(s) of action. TrkA, TrkB, and TrkC, activated by distinct neurotrophins, are high affinity stimulatory receptors. In cancers, activation of Trks, especially of TrkB, are stimulators of cell proliferation, aggressiveness, and metastases. In rare cancers, these processes are due not to receptor activation but to fusion or mutation of the encoding genes. A considerable panel of anti-Trk drugs, developed recently, has been investigated both in vitro and in living mice for their effects on cancer cells. Many such drugs protect from cancers by preventing cell proliferation and inducing apoptosis. At present, these drugs are under control by trials, to promote introduction in human therapy. Moreover, anti-Trk drugs have been employed also in combination with classical chemotherapeutic drugs. So far, studies in mice have been positive. The chemotherapeutic/anti-receptor combinations exhibited in fact increased potency and down-regulation of resistance, with no increase of side effects.

Primary and Metastatic Melanoma With NTRK Fusions

“…Most importantly, however, the fact that NTRK rearrangements and NTRK protein expression can be found in a small subset of cutaneous melanomas using NGS and immunohistochemistry, has relevance for clinical care. Targeting NTRK and NTRK fusions represents a promising new opportunity for cancer treatment(58, 59). Recently, the NTRK inhibitor larotrectinib demonstrated a 78% objective response rate in tumors with NTRK family fusions, regardless of histology(58–61).…”

Targeting the BDNF/TrkB pathway for the treatment of tumors (Review)

“…Initially, neurotrophins and their receptors were thought to be expressed only in nervous system but further studies showed they are also expressed by macrophages, endocrine cells, immune cells, smooth and striated muscle fibers (3,4). Recently, neurotrophins and their Trk receptors, especially BDNF and TrkB, were found to be highly up-regulated and play a vital role in various cancers, including breast, lung, colon-rectum, pancreas, prostate, liver, myelomas and lymphoid tumors (5). Activation of these Trk receptors elicits a series of downstream signalings, including PI3K/Akt, Ras-Raf-MEK-ERK, PLCγ pathway, transactivation of EGFR, etc.…”

Transforming approaches to treating TRK fusion cancer: historical comparison of larotrectinib and histology-specific therapies

“…Larotrectinib is one of the first agents to be studied in a tumor-agnostic manner and receive approval in the United States (US)-and the first to receive approval in the EU; as such, it provides clinicians the first opportunity to understand the clinical development program and basis for comparison for these agents [3,143]. Since the approval of larotrectinib, entrectinib has also received approval based on data from a basket trial in the US [4]. Although both larotrectinib and entrectinib are approved in a tumor-agnostic manner for TRK fusion cancer, larotrectinib is a highly selective has an anti-tumor effect, it will change the natural history of the disease; so, if TTP n is greater than TTP n-1 , then it is likely that the new agent is having an effect on the natural history of that patient's tumor.…”

“…Larotrectinib is the first drug to be approved with a tumor-agnostic indication as the first and only indication. Since the approval of larotrectinib, entrectinib has also received approval in the US and Japan for the treatment of adult and pediatric patients (≥12 years of age) with solid tumors that have an NTRK gene fusion without a known acquired resistance mutation, are metastatic or where surgical resection is likely to result in severe morbidity, and have progressed following treatment or have no satisfactory alternative therapy [4].…”

“…A c c e p t e d M a n u s c r i p t TRK inhibitor, whereas entrectinib is a multi-kinase inhibitor with lower specificity for TRK and also specificity for ROS1 and ALK[3,4,144].There are some drawbacks associated with this type of historical comparison. First, only ORR data is available for larotrectinib by tumor type.…”