# Targeting mTOR in HIV-Negative Classic Kaposi's Sarcoma

Authors: Ofer Merimsky; Irina Jiveliouk; Ronit Sagi-Eisenberg
Journal: Sarcoma
 (2008)

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## Abstract

A 66-year old female with HIV-negative classic Kaposi's sarcoma responded to mTOR targeting by rapamycin. The response was well documented by PET-CT. This case provides supporting evidence that the mTOR pathway may be important in the tumorigenesis of KS and that rapamycin may have activity in this disease.


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## Body

## 1. Introduction

Kaposi's sarcoma (KS) is an indolent vascularized tumor that has been subdivided into several variants including classic
KS, African endemic KS, iatrogenic (post transplantation) KS, and epidemic, acquired immunodeficiency syndrome-associated (AIDS-associated)
KS. It behaves more aggressively in HIV-related or in post transplant patients,
but its classic form may be more indolent although
disfiguring does not commonly result in early mortality. Clinically,
KS forms dark blue or purplish macular lesions or spindle-shaped nodular
lesions that occur in the skin, lymphoid, respiratory, and gastrointestinal
tissues. Histological picture shows networks of spindle-shaped cells and
vascular spaces surrounded by an endothelial cell layer. Therapy for localized
disease is surgery or radiation therapy, while widespread disease may be
treated by systemic chemotherapy [1]. A novel approach for the
treatment of iatrogenic KS is mTOR targeting by rapamycin. Rapamycin is currently
available as an antirejection agent and may be also used as antitumoral therapy [2, 3]. In this paper, we report
a case of HIV-negative classic KS, which responded to mTOR targeting.


## 2. Clinical Case

A 66-year old otherwise healthy
Caucasian female patient presented with metastatic HIV-negative Kaposi's
sarcoma (KS), diffusely involving the skin and soft tissues of the plantar surface, legs,
and thighs. During a prolonged interval of palliative radiation therapy and various
ineffective systemic chemotherapeutic regimens that included vinblastine,
etoposide, doxorubicin, and alpha-interferon. The disease progressed and spread
to the bowel and to the soft tissues of the left arm and to the inguinal,
mediastinal, axillary, and cervical nodes. Clinically, the patient had a
Karnofsky’s performance status of 80–70%, and
complained of weakness, and pain in her lower limbs. Radiologically, the disease was well
documented by PET-CT performed on October 18, 2006 (Figure1). After obtaining
a local IRB approval and signing an informed consent, oral rapamycin was
started according to the following schedule: 1 mg daily in the 1st week, 1 mg twice daily in the 2nd week, 1 mg three times daily in
the 3rd week, and then 1 week off. The next 28-day cycles included
oral rapamycin 1 mg three times daily for 3 out of 4 weeks.
No serum level of rapamycin was obtained as in cases of organ transplantation.
After a 4-week uneventful induction, she moved to 3 mg daily rapamycin. Side effects included
anemia (Hb 9.8 gr/dl), weakness, and mild stomatitis. On January 2007, about 3 months after
treatment initiation, the soft tissue lesions partially regressed, and the
patient mentioned itching in the legs and trunk. PET-CT, performed at the end
of January 2007, demonstrated significant decrease in FDG uptake in almost all
involved sites (Figure 1). The patient is still on treatment for almost 12 months
now.PET-CT at initiation and at completion of
almost 4-month rapamycin therapy.
(a)(b)


## 3. Discussion

Our case points to two important observations. First is the role of mTOR
as a therapeutic target in HIV-negative classic KS. We observed that
rapamycin monotherapy was more active and better tolerated than systemic,
conventional chemotherapy in this patient. The second is monitoring of the
objective response by PET-CT imaging. The clinical improvement correlated with
metabolic shutdown of glucose metabolism in the sarcoma nodules, as documented
by decrease in FDG uptake. PET-CT as a
tool for staging and monitoring of therapy has been suggested for vascular
tumors [4].Rapidly accumulating data
implicate rapamycin, a natural product produced by Streptomyces hygroscopicus
as a potential anticancer agent. While originally identified 20 years ago
during antibiotic screening and found to display remarkable antifungal
activity, rapamycin was subsequently recognized to possess highly potent
immunosuppressive properties [5] and has since been used as
the drug of choice in organ transplantation. More recently, the growth
inhibitory effects of rapamycin have been recognized alongside the elucidation
of the molecular basis of its function. The ultimate cellular target of
rapamycin has been identified as a signaling kinase named “mTOR” (mammalian
target of rapamycin), a member of the phosphatidylinositol-3-kinase
(PI3K)-related kinases (PIKKs). The PIKK family members, also including the ATM
kinase, are involved in the control of essential cell functions, including cell-cycle
progression, cell-cycle check points, DNA repair, and DNA recombination [6]. Specifically, mTOR is a
downstream component in the PI3K/Akt (protein kinase B) pathway, which
participates in the activation of the p70S6 kinase (p70S6k). In response to
mitogenic stimuli, PI3K is activated resulting in a rise in the cellular
concentration of PIP3. This in turn leads to activation of Akt
followed by activation of mTOR. MTOR then phosphorylates and activates p70S6k,
the kinase which phosphorylates the ribosomal protein S6 thereby promoting the
recruitment of the 40S subunit into actively translating polysomes [7]. Following mitogenic
stimulation and activation of mTOR, the latter also phosphorylates the
4E-binding protein-1 (4E-BP1). The latter binds tightly to eIF-4E thereby
preventing initiation of translation. However, upon its mTOR-mediated
phosphorylation, 4E-BP1 dissociates thereby allowing eIF-4E to bind to the
eIF-4F complex and translation increases [8, 9]. Therefore, mTOR
activation results in the transduction signaling events that ultimately
activate cyclin-dependent kinases (CDKs), increase cellular levels of cyclins
such as cyclin D1, and promote retinoblastoma (Rb) protein phosphorylation. As
such, mTOR plays a central role in the control of cell proliferation, cell
survival, and adhesion-independent survival and migration [10, 11].Rapamycin binds to its
intracellular receptor protein FKBP12 [12], forming a complex, which
then binds to and inhibits the function of mTOR [12]. Through mTOR inhibition,
rapamycin causes cell cycle arrest in the G1 phase, prevents CDK activation,
inhibits Rb protein phosphorylation, and accelerates the turnover of cyclin D1,
leading to a deficiency of active CDK4/cyclin D1 complexes. These events then
contribute to the prominent inhibitory effects of rapamycin at the G1/S
boundary of the cell cycle [13]. Notably, rapamycin also
displays antiangiogenic activities linked to a decrease in production of
vascular endothelial growth factor (VEGF) thereby markedly inhibiting response
of vascular endothelial cells to stimulation by VEGF [14].The antiproliferative activity of
rapamycin was first evaluated in variety of murine tumor cell lines and tumor
model systems. In those experiments, rapamycin was found to exhibit impressive
antitumor activity inhibiting the growth of lymphoma cell lines, small cell
lung cancer cell lines, rhabdomyosarcoma cell lines, pancreatic cancer cell
lines and more (reviewed in [15]). Moreover, rapamycin
augmented cisplatin-induced apoptosis [16] and conferred radiation
sensitivity to otherwise resistant tumor cell lines [17]. Taken together, these
results suggest that rapamycin has both intrinsic antiproliferative activity
against a broad range of cancers and the ability to synergize and enhance
efficacy of cytotoxic agents [18]. Indeed, clinical trials
of CCI-779 and Rad 001, structurally related analogs of rapamycin with
increased water solubility, are currently ongoing in recurrent malignant glioma
patients, in renal cell carcinoma, metastatic pancreatic cancer, endometrial
cancer, and more.The role of mTOR signaling pathway in pathogenesis of Kaposi's sarcoma
has been elucidated  [19]. A human herpes virus 8 (HHV8) or
Kaposi's sarcoma associated herpes virus (KSHV) has been suggested as the
etiological agent for this tumor [20]. A single lytic gene, the
KSHV G protein-coupled receptor (vGPCR), a member of the family of CXC
chemokine GPCRs which exhibits ligand-independent activity, has been shown to
be responsible for the initiation of KS [21]. Infection with KSHV is
necessary and central to the development of KS. KSHV infects KS spindle and
endothelial cells in KS lesions, seen eventually in all four forms of KS
(classic (Mediterranean), AIDS-related, endemic (African) and iatrogenic) [22].The
discovery that the development of KS may be dependent on vGPCR dysregulation
suggests that the development of new mechanism-based therapeutic modalities
specifically targeting this viral protein (or its downstream targets) may prove
to be an effective treatment strategy [19]. Several intracellular
proteins, kinases, and transcription factors have been shown to be involved in
vGPCR-expressing cells [19]. It is believed that KSHV
is the putative gene encoding the vGPCR protein that  is responsible for the development of KS, via
dysregulation mechanisms in certain circumstances [19]. It has been suggested
that anti-KS therapy might target the viral protein or the downstream molecules
involved in the KS pathogenesis [19]. The vGPCR leads to
activation of the PI3K/Akt pathway [19]. Activation of Akt was
found to be involved in the protection of endothelial cells from apoptosis,
especially in KSVV-infected
cells [19, 23]. AkT plays an essential
role in the activation of mTOR via inactivation of tuberous sclerosis complex
(TSC) [24, 25]. The TSC/mTOR pathway may
play a critical role in the development of tumors dependent on Akt activation,
and the pathway may be regulated by vGPCR via inactivation of TSC, and
consequent mTOR activation [19]. Other mechanisms for KS
genesis have also been suggested [19].In
conclusion, this case provides supporting evidence that the mTOR pathway may be
important in the tumorigenesis of KS and that rapamycin may have activity in
this disease. A phase II study for assessing the exact role of mTOR inhibitors in
this disease is warranted.



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*Source: 825093-2008-05-15.xml*