FDA approved drugs to treat cancer

Basic mechanism of action proposed

Type of cancers & reference support of mechanism(s) before or after FDA approval

Sipuleucel-T

(Oncophage Vitespen) HSP based cancer vaccines first approved in April, 2010

Person-specific vaccine. In preparation, first HSPs and antigens are isolated from a patient’s cancer cells. The HSP/antigen complexes are made into a vaccination. The patient receives injection once a week. Peptides of HSP member Grp96 to be cross-presented to immunity cells, thereby killing the cancer cells with such recognition.

Prostate cancer according to [172] . Refer to review on mechanism of some prototype vaccines in Section 7.1 and 7.2. Consult discussion on possible non-person- specific, non-cancer-specific vaccine in Section 8.

The drug Gilotrif (afatinib), which is a client protein of HSP90, was approved by FDA on July 2013 to treat non-small-cell-lung cancer. Ganetespib, an HSP90 inhibitor, together with gilotrif as combination of anti-cancer measure in in vivo mice model study is discussed here.

The epidermal growth factor receptor (EGFR) is a tyrosine kinase receptor. HERs are also transmembrane tyrosine kinase receptors. These receptors belong to the ErbB receptor family. They are known to be expressed by, and involved in the growth of a number of cancer cells. Gilotrif was demonstrated to bind the kinase domains of EGFR, HER2 & HER4 and thus irreversibly inhibits tyrosine kinase autophosphorylation, resulting in downregulation of ErbB signaling. However, these kinases are clients of, and binding strongly to HSP90 [173] . It is therefore not surprising that HSP90 inhibitor Ganetespib, combined with inhibitor Gilotrif of such kinases would reduce the synthesis of other HSPs other than HSP90 (because HSP90 is bound to heat shock factor 1; see Figure 2), and would enhance the inhibition of the mTORC1 pathway, causing stronger anti-cancer effects (as compared to the situation using Gilotrif alone) in in vivo mice model study reported [174] , in our opinion.

The support of the drug Gilotrif to treat metastatic non-small cell lung cancer with EGFR mutations is based mainly on the clinical trial reported in [175] . See Sections 2 and 3, with Figure 2 of the present paper on functions of HSP90. See also [176]

OSU-03012 (Ar-12) Pre-Clinical Trial

High level of Akt was frequently detected in brain tumor such as Vestibular schwannoma. At first, this drug was developed from cyclooxygenase-2 inhibitor celecoxib.OSU-03012 is an inhibitor of the upstream protein PDK1, leading to inhibition of protein synthesis induced by the mTORC1 pathway, therefore it could be interpreted effectively as mTOR inhibitor initially.

Brain tumor like Vestibular schwannoma according to [177] [178] . See Section 5.2 with Figure 2 on details of mechanism according to authors’ review opinion.

OSU-03012 (Ar-12)

Clinical Trial, Phase I was announced in 2013 [179]

More recently, it was found that OSU-03012 suppresses HSP70 member GRP78/BiP expression that causes PERK-dependent apoptosis.

The drug was inferred to treat glioblastomas also according to [180] . See Section 5.6 on the PERK-eIF2α-ATF4-CHOP apoptotic signaling machinery for details, according to authors’ review opinion.

Torisel (temsirolimus), approved by FDA in May, 2007; intravenous injection

Interferes with the growth and spread of cancer cells in the body via inhibiting protein synthesis initiated by the mTOR pathway. These proteins include those that regulate progression through the cell cycle. It is also used jointly with interleukin 2 and interferon alpha.

Kidney cancer (metastatic renal cell carcinoma) according to [181] . See Section 5.2 with Figure 2 for the protein synthesis mechanism, and Section 5.3 with Figure 3 on FOXO-translocation induced apoptosis, according to authors’ review opinion.

Afinitor (everolimus), approved by FDA in April 2012, oral

FKBP-12 is an immunophilin and peptidyl-prolyl cis-trans isomerase, and Everolimus binds to FKBP-12, forming a complex. This complex binds to mTORC1 kinase directly, and inhibits the mTORC1 pathway, leading to inhibition of protein synthesis of the cancer cell.

It was approved by FDA to treat renal angiomyolipoma associated with tuberous sclerosis complex, but the study of reference [182] reports that the drug has efficacy on proliferation of giant cell astrotomas, pulmonary and skin lesions associated with tuberous sclerosis complex.