====== Lapatinib ======

Asari et al., investigated the effect of a potent dual [[tyrosine kinase inhibitor]], lapatinib, on [[ACTH]] production and cell proliferation in AtT-20 mouse corticotroph tumor cells. Lapatinib decreased [[proopiomelanocortin]] (Pomc) mRNA levels and ACTH levels in AtT-20 cells and also inhibited cell proliferation, induced apoptosis, and decreased pituitary tumor-transforming gene 1 (Pttg1), a hallmark of pituitary tumors, mRNA levels. KSN/Slc nude mice were subcutaneously inoculated with AtT-20 cells. After 1 week, the mice were randomized either to control or lapatinib groups. The inhibitor decreased the tumor weight of AtT-20 allografts in vivo versus control mice. Lapatinib also significantly decreased Pomc and Pttg1 mRNA levels in the tumor and plasma ACTH and corticosterone levels in vivo. Thus, lapatinib decreases the ACTH production and proliferation of corticotroph tumor cells. An EGFR-targeting therapy could be an important treatment for Cushing's disease
((Asari Y, Kageyama K, Sugiyama A, Kogawa H, Niioka K, Daimon M. Lapatinib
decreases the ACTH production and proliferation of corticotroph tumor cells.
Endocr J. 2019 Mar 15. doi: 10.1507/endocrj.EJ18-0491. [Epub ahead of print]
PubMed PMID: 30880293.
)).

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The efficacy of [[lapatinib]] and [[nilotinib]] in combination with [[radiation therapy]] in a model of [[NF2]] associated peripheral [[schwannoma]].

[[Neurofibromatosis type 2]] (NF2), a neurogenetic condition manifest by [[peripheral nerve sheath tumor]]s (PNST) throughout the [[neuroaxis]] for which there are no approved therapies.

In vitro and in vivo studies presented examine agents targeting [[signaling pathway]]s, [[angiogenesis]], and [[DNA repair]] mechanisms. In vitro dose response assays demonstrated potent activity of [[lapatinib]] and [[nilotinib]] against the mouse schwannoma SC4 (Nf2 -/-) cell line. 

Paldor et al. examined the efficacy of [[everolimus]], [[nilotinib]], [[lapatinib]], [[bevacizumab]] and [[radiotherapy]] (RT) as mono- and combination therapies in flank and sciatic nerve in vivo NF2-PNST models. Data were analyzed using generalized linear models, two sample T-tests and paired T-tests, and linear regression models. SC4(Nf2 -/-) cells implanted in the flank or sciatic nerve showed similar rates of growth (p = 0.9748). Lapatinib, nilotinib and RT significantly reduced tumor growth rate versus controls in the in vivo flank model (p = 0.0025, 0.0062, and 0.009, respectively) whereas bevacizumab and everolimus did not. The best performers were tested in the in vivo sciatic nerve model of NF2 associated PNST, where chemoradiation outperformed nilotinib or lapatinib as single agents (nilotinib vs. nilotinib + RT, p = 0.0001; lapatinib versus lapatinib + RT, p < 0.0001) with no observed toxicity. There was no re-growth of tumors even 14 days after treatment was stopped. The combination of either lapatinib or nilotinib with RT resulted in greater delays in tumor growth rate than any modality alone. This data suggest that concurrent low dose RT and targeted therapy may have a role in addressing progressive PNST in patients with NF2
((Paldor I, Abbadi S, Bonne N, Ye X, Rodriguez FJ, Rowshanshad D, Itzoe M,
Vigilar V, Giovannini M, Brem H, Blakeley JO, Tyler BM. The efficacy of lapatinib
and nilotinib in combination with radiation therapy in a model of NF2 associated 
peripheral schwannoma. J Neurooncol. 2017 Jul 22. doi: 10.1007/s11060-017-2567-9.
[Epub ahead of print] PubMed PMID: 28735458.
)).

Lapatinib is presumed to cross the [[blood brain barrier]], and exhibits clinical activities for treatment of HER2 positive breast cancer. A 43-year-old woman was treated for early breast carcinoma with total mastectomy, axillary lymph-node dissection, and adjuvant chemotherapy with cyclophosphamide plus doxorubicin. After the end of adjuvant trastuzumab therapy, she was diagnosed with panhypopituitarism due to pituitary metastasis. Surgical removal and whole brain radiation therapy were performed, but a portion of viable tumor remained. Only taking lapatinib, the size of the metastatic lesion began to shrink. Trastuzumab may have controlled the micro-metastasis of breast cancer, but it was unable to control its progression to the central nervous system. Lapatinib is a possible option for [[HER2 positive breast cancer  brain metastases]]
((Park Y, Kim H, Kim EH, Suh CO, Lee S. Effective Treatment of Solitary
Pituitary Metastasis with Panhypopituitarism in HER2-Positive Breast Cancer by
Lapatinib. Cancer Res Treat. 2015 Feb 16. doi: 10.4143/crt.2014.165. [Epub ahead 
of print] PubMed PMID: 25715765.
)).