New anticancer nanoparticle drug containing small interfering RNAs

Agents tageting small interfering RNAs (siRNA) for use in cancer have been developed. The phase 1 clinical trials are over and the results were recently published in Nature.

CALAA-01 is a nanoparticle drug containing small interfering RNAs targeted to ribonucleside reductase M2. This is used in solid tumors that are refractory to therapy.

This opens an entirely new class of anticancer agents.

New screening method for Anticancer drugs

Many researchers believe tumour growth is driven by cancerous stem cells that, for reasons not yet understood, are highly resistant to standard treatments. Chemotherapeutic agents may kill off 99 percent of the cells in a tumor, but the stem cells that remain can make the cancer recur or spread to other tissues in the body to cause new cancers.

Stem cells, unlike mature cells, can constantly renew themselves and are thought to be the source of cancers when, through mutations in their DNA, they throw off their natural restraints.
a team at the Broad Institute devised a way of screening for drugs that attack cancer stem cells but leave ordinary cells unharmed.

Cancer stem cells are hard to maintain in sufficient numbers, but the Broad Institute team devised a genetic manipulation to keep breast cancer stem cells trapped in the stem cell state.

The team, led by Piyush B. Gupta, screened some 16,000 chemicals, including all known chemotherapeutic agents approved by the FDA. The team reported in the Cell that 32 of the chemicals selectively went after cancer stem cells. The screening system proves for the first time that it is possible to single out cancer stem cells with drugs that leave ordinary cells alone. Only one of the 32 chemicals is approved as a drug for cancer.

Another approach to concentrating on cancer stem cells, based on the use of antibodies, was reported this month by OncoMed Pharmaceuticals.

The cancer stem cell theory has been thrust into the spotlight in the last five years with the discovery of stem cells in many types of solid tumors, including those of the breast, brain, prostate, colon, bladder and pancreas.

Source: http://www.nytimes.com/2009/08/14/health/research/14cancer.html?_r=1&8au&emc=au

Novel agents and approaches for breast cancer

Cytotoxic chemotherapy remains an important part of the treatment paradigm for breast cancer. Anthracyclines and taxanes are the most active agents; however, limitations with their use include a maximum lifetime dose and tumor resistance with anthracycline, hypersensitivity reactions and cumulative toxicity with taxanes.

• Therefore, to meet these challenges, the development of new cytotoxics and novel taxane formulations is an important area of active research. Several recent advances have been made. Epothilones represent a novel group of cytotoxic agents, with proven activity in breast cancer.
• Nanoparticle drug delivery systems have led to the development of ABI-007, which has demonstrated superior response rates than 3-weekly paclitaxel, with a lower risk of hypersensitivity reactions.
• To circumvent the problem of taxane resistance, larotaxel, a semisynthetic taxoid, and vinflunine, a synthetic vinca alkaloid, have been developed with encouraging clinical results to date.
• Eribulin, a synthetic derivative of halichondrin has recently entered Phase III trials based on encouraging activity in heavily pretreated patients.
• A further novel approach is the conjugation of cytotoxic agents to targeted agents, such as with trastuzumab-MCC-DM1.

Hepatocellular carcinoma: Promising results of dendritic cell-based immunotherapy

HCC is a promising target for immunotherapy because tumor-infiltrating lymphocytes are actively recruited to HCC lesions. However, these lymphocytes fail to kill tumor cells, possibly because T-cell maturation is prevented.
Dendritic cells process antigens and present them to naive T and B cells. Dr Palmer et al. isolated dendritic cells from 35 patients with advanced HCC who were not amenable to curative resection, transplantation, local ablation or chemoembolization. Dendritic cells were pulsed with lysates from Hep G2, a liver-tumor cell line with many antigens in common with HCC. Patients received well-tolerated, multiple intravenous infusions of mature, pulsed dendritic cells. Of 25 patients who received at least two vaccinations, one achieved radiological partial response and six disease stabilization for 6–16 months. Of the 17 patients eligible for serological assessment, four achieved partial serological response and four disease stabilization.

Source: Palmer, D. H. et al. A phase II study of adoptive immunotherapy using dendritic cells pulsed with tumor lysate in patients with hepatocellular carcinoma. Hepatology 49, 124–132 (2009).

Targeted cancer therapy

Treatment options for inoperable or progressive malignant pancreatic endocrine tumors (PETs) are limited, but new evidence suggests that the epidermal growth factor receptor (EGFR) and cyclo-oxygenase 2 (COX2) should be investigated as potential chemotherapeutic targets.

Dr Bergmann et al. analyzed 110 tumor samples from 74 patients who underwent resection of PETs between 1991 and 2006. EGFR was expressed in 57% of malignant PETs and in 26% of nonmalignant (benign tumors or those with uncertain behavior) PETs. Malignant PETs were characterized by significantly higher average expression of EGFR than nonmalignant PETs. By contrast, no significant differences were observed between nonmalignant and malignant PETs regarding COX2 expression, which was uniformly high across tumor categories.
Administration of the EGFR antagonist AG1478 and of the COX2 inhibitor celecoxib to the human pancreatic carcinoid cell line BON and to the mouse pancreatic insulinoma cell line -TC-3 resulted in significant, dose-dependent decreases of cell viability. Administered in combination, celecoxib and AG1478 displayed additive effects on cell viability in both cell lines.
Evidence suggests that EGFR and COX2 are potential chemotherapeutic targets for PETs that should be further investigated.

Source: Bergmann, F. et al. Expression pattern and functional relevance of epidermal growth factor receptor and cyclooxygenase-2: novel chemotherapeutic targets in pancreatic endocrine tumors? Am. J. Gastroenterol. 104, 171–181 (2009).

Marked Decline in Breast Cancer Risk After Stopping Contraceptive pills

Following the release of the 2002 report of the Women's Health Initiative (WHI) trial of estrogen plus progestin (EPT), the use of menopausal hormone therapy in the United States decreased substantially. Subsequently, the incidence of breast cancer also dropped, suggesting a cause-and-effect relation between hormone treatment and breast cancer.

In a study published in N Engl J Med 2009, Leon Speroff, MD and Wendy Y. Chen, MD, MPH analyzed the results of the WHI randomized clinical trial—in which one study group received 0.625 mg of conjugated equine estrogens plus 2.5 mg of medroxyprogesterone acetate daily and another group received placebo—and examined temporal trends in breast-cancer diagnoses in the WHI observational-study cohort. Risk factors for breast cancer, frequency of mammography, and time-specific incidence of breast cancer were assessed in relation to combined hormone use.

RESULTS: In the clinical trial, there were fewer breast-cancer diagnoses in the group receiving estrogen plus progestin than in the placebo group in the initial 2 years of the study, but the number of diagnoses increased over the course of the 5.6-year intervention period. The elevated risk decreased rapidly after both groups stopped taking the study pills, despite a similar frequency of mammography. In the observational study, the incidence of breast cancer was initially about two times as high in the group receiving menopausal hormones as in the placebo group, but this difference in incidence decreased rapidly in about 2 years, coinciding with year-to-year reductions in combined hormone use. During this period, differences in the frequency of mammography between the two groups were unchanged.

The authors concluded that increased risk of breast cancer associated with the use of estrogen plus progestin declined markedly soon after discontinuation of combined hormone therapy and was unrelated to changes in frequency of mammography.

This report from the WHI is not the first about the change in breast cancer prevalence that occurred after the initial WHI publications in 2002, but it is of value because it documents that the change cannot be attributed solely to a decrease in the use of mammography.

The WHI recently updated results on breast cancer risk after discontinuation of the combination EPT arm. Overall results were published for the post-intervention phase in 2008. With mean follow-up of 2.4 years for this phase, a nonsignificant increased risk of breast cancer was still observed (HR, 1.27; 95% CI, 0.91-1.78), with a possible downward trend in cancer risk with follow-up.

This newest report is a more detailed analysis on breast cancer outcomes and also drew data from the observational cohort of the WHI. HRs for 6-month time intervals were calculated for both the intervention and nonintervention phase of the clinical trial. In an intention-to-treat analysis, there was no difference in the slopes of the HRs over time comparing the intervention and post-intervention phases (P = 0.28). However, after adjusting for adherence by censoring nonadherent subjects, there was a statistically significant difference in the slopes with HRs increasing over time for women using EPT, but declining after discontinuation (P = 0.005). Although breast cancer cases appeared to decline more in the intervention arm compared to placebo, mammography rates were similar in both arms. During the post-intervention phase, both breast biopsies and mammograms with abnormalities were more common in the EPT arm compared to placebo. Similar results for breast cancer incidence rates were seen using the observational data, although mammography rates were higher among women who used HT compared to those who did not.

After the WHI results were released in 2002, there was a large decline in HT use in the United States. Several investigators then reported a decline in US breast cancer rates correlating with reporting of the WHI trial results. Given the temporal association, it was speculated that this decrease in breast cancer incidence may have been due to the widespread discontinuation of HT, although other investigators noted that there was also a concomitant decline in mammography utilization, which may also have explained the changes. However, mammography rates were similar in the intervention arms of the WHI trial and were stable over time for women in the observational study, so it would seem unlikely that changes in mammography utilization alone can explain the recent decline in US breast cancer rates.

Angiostatic Approach to Cancer Therapy

Various inhibitors of angiogenesis are under investigation in patients with
advanced cancer:


Drugs that block matrix breakdown:
1. Marimastat

against
pancreas,
non-small
cell lung,
breast
cancers
Synthetic inhibitor of
matrix
metalloproteinases
(MMPs)
2. Bay 12-9566

against lung,
ovary, and
pancreatic
cancers
Synthetic inhibitor of
tumor growth
3. AG3340

against
non-small
cell lung;
against
prostate
cancer
Synthetic MMP
inhibitor



4. CGS
27023A

Synthetic MMP inhibitor
5. COL-3

Synthetic MMP
inihibitor.
Tetracycline derivative
6. Neovastat

against
non-small
cell lung
cancer
Naturally occurring
MMP inhibitor
7. BMS-275291

Synthetic MMP
Inhibitor
8. Dalteparin
9. Suramin



Drugs that inhibit endothelial cells directly:

1. TNP-470

against
advanced
cancer for
adults with
solid tumors;
against
pediatric solid
tumors,
lymphomas,
and acute
leukemias
Synthetic
analogue of
fumagillin; inhibits
endothelial cell
growth
2. Thalidomide

against
Kaposi's
sarcoma,
glioblastoma,
prostate, lung,
and breast
cancers
Mech. unknown
3. Squalamine

Extract from
dogfish shark liver;
inhibits
sodium-hydrogen
exchanger, NHE3
4. Combretastatin

Induction of
apoptosis in
proliferating
endothelial cells
5. Endostatin

solid
tumor
Inhibition of
endothelial cells

6. 2-methoxyestradiol
(2-ME)
7. CC-5013 (Thalidomide Analog)
8. LY317615 (Protein Kinase C Beta Inhibitor)
9.Soy Isoflavone (Genistein; Soy Protein Isolate)

Drugs that block activators of angiogenesis:

1. Anti-VEGF Antibody
against lung,
breast,
prostate,
colorectal, and
renal cancers
Monoclonal
antibody to
vascular
endothelial
growth factor
(VEGF)



2. SU5416

against
Kaposi's
sarcoma,
against
metastatic
colorectal
cancer, and
against
advanced
malignancies
Blocks VEGF
receptor
signaling
3. SU6668

against
advanced
tumors
Blocks VEGF,
FGF, and EGF
receptor
signaling





4. PTK787/ZK
22584

against
advanced
cancers
against
glioblastoma
and Kaposi's
sarcoma;
against Von
Hippel Lindau
disease
Blocks VEGF
receptor
signaling
5. Interferon-alpha
Commercially
Available

Inhibition of
bFGF and
VEGF
production



Drugs that inhibit endothelial-specific integrin/survival signaling:

1. Vitaxin

Antibody to
integrin present
on endothelial
cell surface
2. EMD121974

against Kaposi's
sarcoma, brain
tumors, and
solid tumors
Small molecule
blocker of integrin
present on
endothelial cell
surface

Drugs with non-specific mechanism of action:
1. CAI

against ovarian,
non-small cell
lung, and renal
cell cancers
Inhibitor of
calcium influx
2. Interleukin-12
against Kaposi's
sarcoma and
solid tumors
Up-regulation of
interferon gamma
and IP-10
3. IM862
Against AIDS-related
Kaposi's
sarcoma
Unknown
mechanism

Antiangiogenic therapy combined with conventional anticancer therapies may represent an useful tool in the future care of patients with cancer.